Inhibitors of farnesyl-protein transferase

ABSTRACT

The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit farnesyl-protein transferase. Furthermore, these CAAX analogues differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

RELATED APPLICATIONS

The present patent application is a continuation-in-part of copendingPCT Application No. PCT/US95/12474, filed Oct. 27, 1995, and acontinuation-in-part application of application Ser. No. 08/527,972,filed Sep. 14, 1995, now U.S. Pat. No. 5,661,161, which is acontinuation-in-part application of Ser. No. 08/472,077, filed Jun. 6,1995, now abandoned, which is a continuation-in-part application of Ser.No. 08/399,282, filed Mar. 6, 1995, now abandoned, which is acontinuation-in-part application Ser. No. 08/315,161, filed Sep. 29,1994, now abandoned.

BACKGROUND OF THE INVENTION

The Ras protein is part of a signalling pathway that links cell surfacegrowth factor receptors to nuclear signals initiating cellularproliferation. Biological and biochemical studies of Ras action indicatethat Ras functions like a G-regulatory protein. In the inactive state,Ras is bound to GDP. Upon growth factor receptor activation Ras isinduced to exchange GDP for GTP and undergoes a conformational change.The GTP-bound form of Ras propagates the growth stimulatory signal untilthe signal is terminated by the intrinsic GTPase activity of Ras, whichreturns the protein to its inactive GDP bound form (D. R. Lowy and D. M.Willumsen, Ann. Rev. Biochem. 62:851-891 (1993)). Mutated ras genes arefound in many human cancers, including colorectal carcinoma, exocrinepancreatic carcinoma, and myeloid leukemias. The protein products ofthese genes are defective in their GTPase activity and constitutivelytransmit a growth stimulatory signal.

Ras must be localized to the plasma membrane for both normal andoncogenic functions. At least 3 post-translational modifications areinvolved with Ras membrane localization, and all 3 modifications occurat the C-terminus of Ras. The Ras C-terminus contains a sequence motiftermed a "CAAX" or "Cys-Aaa¹ -Aaa² -Xaa" box (Cys is cysteine, Aaa is analiphatic amino acid, the Xaa is any amino acid) (Willumsen et al.,Nature 310:583-586 (1984)). Depending on the specific sequence, thismotif serves as a signal sequence for the enzymes farnesyl-proteintransferase or geranylgeranyl-protein transferase, which catalyze thealkylation of the cysteine residue of the CAAX motif with a C₁₅ or C₂₀isoprenoid, respectively. (S. Clarke., Ann. Rev. Biochem. 61:355-386(1992); W. R. Schafer and J. Rine, Ann. Rev. Genetics 30:209-237(1992)). The Ras protein is one of several proteins that are known toundergo post-translational farnesylation. Other farnesylated proteinsinclude the Ras-related GTP-binding proteins such as Rho, fungal matingfactors, the nuclear lamins, and the gamma subunit of transducin. James,et al., J. Biol. Chem. 269, 14182 (1994) have identified a peroxisomeassociated protein Pxf which is also farnesylated. James, et al., havealso suggested that there are farnesylated proteins of unknown structureand function in addition to those listed above.

Inhibition of farnesyl-protein transferase has been shown to block thegrowth of Ras-transformed cells in soft agar and to modify other aspectsof their transformed phenotype. It has also been demonstrated thatcertain inhibitors of farnesyl-protein transferase selectively block theprocessing of the Ras oncoprotein intracellularly (N. E. Kohl et al.,Science, 260:1934-1937 (1993) and G. L. James et al., Science,260:1937-1942 (1993). Recently, it has been shown that an inhibitor offarnesyl-protein transferase blocks the growth of ras-dependent tumorsin nude mice (N. E. Kohl et al., Proc. Natl. Acad. Sci U.S.A.,91:9141-9145 (1994) and induces regression of mammary and salivarycarcinomas in ras transgenic mice (N. E. Kohl et al., Nature Medicine,1:792-797 (1995).

Indirect inhibition of farnesyl-protein transferase in vivo has beendemonstrated with lovastatin (Merck & Co., Rahway, N.J.) and compactin(Hancock et al., ibid; Casey et al., ibid; Schafer et al., Science245:379 (1989)). These drugs inhibit HMG-CoA reductase, the ratelimiting enzyme for the production of polyisoprenoids including farnesylpyrophosphate. Farnesyl-protein transferase utilizes farnesylpyrophosphate to covalently modify the Cys thiol group of the Ras CAAXbox with a farnesyl group (Reiss et al., Cell, 62:81-88 (1990); Schaberet al., J. Biol. Chem., 265:14701-14704 (1990); Schafer et al., Science,249:1133-1139 (1990); Manne et al., Proc. Natl. Acad. Sci USA,87:7541-7545 (1990)). Inhibition of farnesyl pyrophosphate biosynthesisby inhibiting HMG-CoA reductase blocks Ras membrane localization incultured cells. However, direct inhibition of farnesyl-proteintransferase would be more specific and attended by fewer side effectsthan would occur with the required dose of a general inhibitor ofisoprene biosynthesis.

Inhibitors of farnesyl-protein transferase (FPTase) have been describedin two general classes. The first are analogs of farnesyl diphosphate(FPP), while the second class of inhibitors is related to the proteinsubstrates (e.g., Ras) for the enzyme. The peptide derived inhibitorsthat have been described are generally cysteine containing moleculesthat are related to the CAAX motif that is the signal for proteinprenylation. (Schaber et al., ibid; Reiss et. al., ibid; Reiss et al.,PNAS, 88:732-736 (1991)). Such inhibitors may inhibit proteinprenylation while serving as alternate substrates for thefarnesyl-protein transferase enzyme, or may be purely competitiveinhibitors (U.S. Pat. No. 5,141,851, University of Texas; N. E. Kohl etal., Science, 260:1934-1937 (1993); Graham, et al., J. Med. Chem., 37,725 (1994)). In general, deletion of the thiol from a CAAX derivativehas been shown to dramatically reduce the inhibitory potency of thecompound. However, the thiol group potentially places limitations on thetherapeutic application of FPTase inhibitors with respect topharmacokinetics, pharmacodynamics and toxicity. Therefore, a functionalreplacement for the thiol is desirable.

It has recently been shown that farnesyl-protein transferase inhibitorsare inhibitors of proliferation of vascular smooth muscle cells and aretherefore useful in the prevention and thereapy of arteriosclerosis anddiabetic disturbance of blood vessels (JP H7-112930).

With the exception of the pepticinnamins, non-thiol FPTase inhibitorsthat are competitive with the Ras substrate have not been described andare the subject of this invention.

It is, therefore, an object of this invention to developtetrapeptide-based compounds which do not have a thiol moiety, and whichwill inhibit farnesyl transferase and the post-translationalfunctionalization of the oncogene Ras protein. It is a further object ofthis invention to develop chemotherapeutic compositions containing thecompounds of this invention and methods for producing the compounds ofthis invention.

SUMMARY OF THE INVENTION

The present invention comprises analogs of the CAAX motif of the proteinRas that is modified by farnesylation in vivo. These CAAX analogsinhibit the farnesyl-protein transferase. Furthermore, these CAAXanalogues differ from those previously described as inhibitors offarnesyl-protein transferase in that they do not have a thiol moiety.The lack of the thiol offers unique advantages in terms of improvedpharmacokinetic behavior in animals, prevention of thiol-dependentchemical reactions, such as rapid autoxidation and disulfide formationwith endogenous thiols, and reduced systemic toxicity. The compounds ofthe instant invention also incorporate a cyclic amine moiety in thesecond amino acid position of the motif. Further contained in thisinvention are chemotherapeutic compositions containing these farnesyltransferase inhibitors and methods for their production.

The compounds of this invention are illustrated by the formulae:##STR1##

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention inhibit farnesyl-protein transferase. Ina first embodiment of this invention, the farnesyl-protein transferaseinhibitors are illustrated by the formula I: ##STR2## wherein: R^(1a)and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclic, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰ --;

R^(2a) and R^(2b) are independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆ alkenyl, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R³ and R⁴ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R³ and R⁴ are combined to form --(CH₂)_(s) --;

R^(5a) and R^(5b) are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocycle group,

wherein the substituent is selected from F, Cl, Br, CF₃, N(R¹⁰)₂, NO₂,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R^(5a) and R^(5b) are combined to form --(CH₂)_(s) -- wherein one of thecarbon atoms is optionally replaced by a moiety selected from: O,S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

X--Y is ##STR3## R^(7a) is selected from a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl;

R^(7b) is selected from

a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl,

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl,

f) a carbonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, and

g) a sulfonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C--(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from H, C₁ -C₆ alkyl, benzyl, substitutedaryl and C₁ -C₆ alkyl substituted with substituted aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif

A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a second embodiment of this invention the prodrugs of compounds offormula I are illustrated by the formula II: ##STR4## wherein: R^(1a)and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclic, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰ --;

R^(2a) and R^(2b) are independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆ alkenyl, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R³ and R⁴ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R³ and R⁴ are combined to form --(CH₂)_(s) --;

R^(5a) and R^(5b) are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocycle group,

wherein the substituent is selected from F, Cl, Br, CF₃, N(R¹⁰)₂, NO₂,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R^(5a) and R^(5b) are combined to form --(CH₂)_(s) -- wherein one of thecarbon atoms is optionally replaced by a moiety selected from: O,S(O)_(m), --NC(O)--, and --N(COR¹⁰)--;

R⁶ is

a) substituted or unsubstituted C₁ -C₈ alkyl, substituted orunsubstituted C₅ -C₈ cycloalkyl, or substituted or unsubstituted cyclicamine, wherein the substituted alkyl, cycloalkyl or cyclic amine issubstituted with 1 or 2 substituents independently selected from:

1) C₁ -C₆ alkyl,

2) aryl,

3) heterocycle,

4) --N(R¹¹)₂,

5) --OR¹⁰, or

b) ##STR5## R^(7a) is selected from a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl;

R^(7b) is selected from

a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl,

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl,

f) a carbonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, and

g) a sulfonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C--(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from H, C₁ -C₆ alkyl, benzyl, substitutedaryl and C₁ -C₆ alkyl substituted with substituted aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is hydrogen or C₁ -C₆ alkyl;

R¹³ is C₁ -C₆ alkyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif

A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a third embodiment of this invention, the inhibitors offarnesyl-protein transferase are illustrated by the formula III:##STR6## wherein: R^(1a) and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocyclic, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰ --;

R^(2a) and R^(2b) are independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆ alkenyl, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R³ and R⁴ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R³ and R⁴ are combined to form --(CH₂)_(s) --;

X--Y is ##STR7## R^(7a) is selected from a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl;

R^(7b) is selected from

a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl,

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl,

f) a carbonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, and

g) a sulfonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ OC(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C--(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from H, C₁ -C₆ alkyl, benzyl, substitutedaryl and C₁ -C₆ alkyl substituted with substituted aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is hydrogen or C₁ -C₆ alkyl;

R¹³ is C₁ -C₆ alkyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif

A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a fourth embodiment of this invention the prodrugs of compounds offormula III are illustrated by the formula IV: ##STR8## wherein: R^(1a)and R^(1b) are independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰--,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰ --;

R^(2a) and R^(2b) are independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆ alkenyl, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R³ and R⁴ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocycle group,

wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ C(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or

R³ and R⁴ are combined to form --(CH₂)_(s) --;

X--Y is ##STR9## R^(7a) is selected from a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl;

R^(7b) is selected from

a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl,

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl,

f) a carbonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, and

g) a sulfonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R⁸ is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, N(R¹⁰)₂, or R¹⁰ OC(O)NH--;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C--(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR ¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by perfluoroalkyl, F, Cl,Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from H, C₁ -C₆ alkyl, benzyl, substitutedaryl and C₁ -C₆ alkyl substituted with substituted aryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is hydrogen or C₁ -C₆ alkyl;

R¹³ is C₁ -C₆ alkyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl,

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif

A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0, 1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

s is 4 or 5;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a more preferred embodiment of this invention, the farnesyl-proteintransferase inhibitors are illustrated by the Formula I: ##STR10##wherein: R^(1a) is independently selected from: hydrogen or C₁ -C₆alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R^(2a) is selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆ alkenyl, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(2b) is hydrogen;

R³ and R⁴ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R^(5a) is selected from:

a) a side chain of a naturally occurring amino acid, wherein the aminoacid is selected from methionine and glutamine,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, CF₃, NO₂, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R^(5b) is selected from:

a) hydrogen, and

b) C₁ -C₃ alkyl;

X--Y is ##STR11## R^(7a) is selected from a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl;

wherein heterocycle is selected from pyrrolidinyl, imidazolyl,pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl;

R^(7b) is selected from

a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl,

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl,

f) a carbonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, and

g) a sulfonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; whereinheterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR ¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R ¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, C--(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif

A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a second more preferred embodiment of this invention, the prodrugs ofthe preferred compounds of Formula I are illustrated by the Formula II:##STR12## wherein: R^(1a) is independently selected from: hydrogen or C₁-C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R^(2a) is selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted by C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(2b) is hydrogen;

R³ and R⁴ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R^(5a) is selected from:

a) a side chain of a naturally occurring amino acid, wherein the aminoacid is selected from methionine and glutamine,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone, and

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,

wherein the substituent is selected from F, Cl, Br, CF₃, NO₂, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

R^(5b) is selected from:

a) hydrogen, and

b) C₁ -C₃ alkyl;

R⁶ is

a) substituted or unsubstituted C₁ -C₈ alkyl, substituted orunsubstituted C₅ -C₈ cycloalkyl, or substituted or unsubstituted cyclicamine wherein the substituted alkyl, cycloalkyl or cyclic amine issubstituted with 1 or 2 substituents independently selected from:

1) C₁ -C₆ alkyl,

2) aryl,

3) heterocycle,

4) --N(R¹¹)₂,

5) -OR¹⁰, or ##STR13## X--Y is ##STR14## R^(7a) is selected from a)hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle, d) unsubstituted orsubstituted C₃ -C₁₀ cycloalkyl, and

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl; wherein heterocycle is selected from pyrrolidinyl,imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,quinolinyl, isoquinolinyl, and thienyl;

R^(7b) is selected from

a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl,

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl,

f) a carbonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, and

g) a sulfonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; whereinheterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ O--, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂,or R¹¹ OC(O)NR¹⁰ --;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

R¹² is hydrogen or C₁ -C₆ alkyl;

R¹³ is 1,1-dimethylethyl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N,

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif

A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

r is 0 to 5, provided that r is 0 when V is hydrogen;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a third more preferred embodiment of this invention, the inhibitorsof farnesyl-protein transferase are illustrated by the formula III:##STR15## wherein: R^(1a) is independently selected from: hydrogen or C₁-C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R^(2a) is selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆ alkenyl, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(2b) is hydrogen;

R³ and R⁴ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocycle group,

wherein the substituent is selected from F, Cl, Br, --NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

X--Y is ##STR16## R^(7a) is selected from a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl;

wherein heterocycle is selected from pyrrolidinyl, imidazolyl,pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl;

R^(7b) is selected from

a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl,

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl,

f) a carbonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, and

g) a sulfonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; whereinheterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R ¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif

A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

Z is independently H₂ or O;

m is 0, 1 or 2;

n is 0, 1, 2, 3 or 4;

p is 0, 1, 2, 3 or 4;

q is 0,1 or 2;

r is 0 to 5, provided that r is 0 when V is hydrogen;

t is 3, 4 or 5; and

u is 0 or 1;

or the pharmaceutically acceptable salts thereof.

In a fourth more preferred embodiment of this invention, the prodrugs ofthe preferred compounds of Formula III are illustrated by the FormulaIV: ##STR17## wherein: R^(1a) is independently selected from: hydrogenor C₁ -C₆ alkyl;

R^(1b) is independently selected from:

a) hydrogen,

b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆alkenyl,

c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ;

R^(2a) is selected from:

a) hydrogen,

b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆ alkenyl, R¹⁰ O--,R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,

c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR ¹⁰ --, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl;

R^(2b) is hydrogen;

R³ and R⁴ are independently selected from:

a) a side chain of a naturally occurring amino acid,

b) an oxidized form of a side chain of a naturally occurring amino acidwhich is:

i) methionine sulfoxide, or

ii) methionine sulfone,

c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocycle group,

wherein the substituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and

d) C₁ -C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;

X--Y is ##STR18## R^(7a) is selected from a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl;

wherein heterocycle is selected from pyrrolidinyl, imidazolyl,pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl;

R^(7b) is selected from

a) hydrogen,

b) unsubstituted or substituted aryl,

c) unsubstituted or substituted heterocycle,

d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl,

e) C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl,

f) a carbonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, and

g) a sulfonyl group which is bonded to an unsubstituted or substitutedgroup selected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆alkyl substituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; whereinheterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl;

R⁸ is independently selected from:

a) hydrogen,

b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR ¹⁰ --, and

c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --;

R⁹ is selected from:

a) hydrogen,

b) C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and

c) C₁ -C₆ alkyl unsubstituted or substituted by C₁ -C₆ perfluoroalkyl,F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --;

R¹⁰ is independently selected from hydrogen, C₁ -C₆ alkyl, benzyl andaryl;

R¹¹ is independently selected from C₁ -C₆ alkyl and aryl;

A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, or S(O)_(m) ;

V is selected from:

a) hydrogen,

b) heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl,

c) aryl,

d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replaced with a aheteroatom selected from O, S, and N, and

e) C₂ -C₂₀ alkenyl, and

provided that V is not hydrogen if A¹ is S(O)_(m) and V is not hydrogenif

A¹ is a bond, n is 0 and A² is S(O)_(m) ;

W is a heterocycle selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl, orisoquinolinyl;

Z is independently H₂ or O;

    ______________________________________    m is      0, 1 or 2;    n is      0, 1, 2, 3 or 4;    p is      0, 1, 2, 3 or 4;    q is      0, 1 or 2;    r is      0 to 5, provided that r is 0 when V is hydrogen;    t is      3, 4 or 5; and    u is      0 or 1;    ______________________________________

or the pharmaceutically acceptable salts thereof.

The preferred compounds of this invention are as follows:

N-1-(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(2(S),3-Diaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(2(S),3-Diaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(3-Aminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(3-Aminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N- 1-(2(S)-Amino-3-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(2(S)-Amino-3-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methyl ester

N- 1-(3-Amino-2(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(3-Amino-2(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methyl ester

N- 1-(L-Glutaminyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(L-Glutaminyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methyl ester

N-1-(L-Histidyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(L-Histidyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(D-Histidyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(D-Histidyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methionine

2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester

2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methionineisopropyl ester

2(S)-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methionine

2(S)-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester

2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninesulfone

2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninesulfone methyl ester

2(S)-1-(Pyrid-3-ylcarboxy)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methionine

2(S)-1-(Pyrid-3-ylcarboxy)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester

2(R)-{2-1-(Naphth-2-yl)-1-H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine

2(R)-{2-1-(Naphth-2-yl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methioninemethyl ester

2(S)-1-(Pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methionine

2(S)-1-(Pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester

N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninesulfone isopropyl ester

N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninesulfone

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine sulfonemethyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine sulfone

N- 1-(Sarcosyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

N- 1-(Sarcosyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(N,N-Dimethylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

N- 1-(N,N-Dimethylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(Glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N- 1-(Glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(2-Acetylamino-3(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(2-Acetylamino-3(S)-aminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(2-Amino-3(S)-acetylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

2(S)-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester

2(S)- 1-(1H-imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2-(S)-ylmethyloxy!-3-phenylpropionyl-methionine

2(R)-{2-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine methyl ester

2(R)-{2-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine

2(R)-{2-1-(4-Nitrobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine methyl ester

2(R)-{2-1-(4-Nitrobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine

2(R)-{2-1-(4-Methoxybenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine methyl ester

2(R)-{2-1-(4-Methoxybenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine

2(R)-{2-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-3(S)-ethyl-2(S)-ylmethoxy}-3-phenylpropionyl-methionine methyl ester

2(R)-{2-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-3(S)-ethyl-2(S)-ylmethoxy}-3-phenylpropionyl-methionine

N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninemethyl ester

N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alanine

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninemethyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alanine

N-1-(Seryl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N- 1-(D-Alanyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

N-1-(1H-imidazol-4-carbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N- 1-(Isoasparagyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

N- 1-(1H-Imidazol-4-propionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

N- 1-(3-Pyridylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

N- 1-(2-Pyridylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

N- 1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

N-1-(Seryl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(D-Alanyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(1H-Imidazol-4-carbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(Isoasparagyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(1H-Imidazol-4-propionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(3-Pyridylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(2-Pyridylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylmethyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(2-Aminoethyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(2-thienyl)alanine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(trifluoromethyl)alanine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(2(S)-amino-4-acetylamino)butyricacid

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(N,N-dimethyl)glutamine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(benzyl)glycyl-methionine

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(benzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(4-methoxybenzyl)glycyl-methionine

N-1-(Glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(benzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(benzyl)glycyl-methionine

N-((4-Imidazolyl)methyl-(2S)-pyrrolidinylmethyl)-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(2-thienyl)alaninemethyl ester

N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(N,N-dimethyl)glutaminemethyl ester

N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(trifluoromethyl)alaninemethyl ester

N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(2(S)-amino-4-acetylamino)butyricacid methyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(benzyl)glycyl-methioninemethyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(benzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(4-methoxybenzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(benzyl)glycyl-methioninemethyl ester

N- 1-(Glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(benzyl)glycyl-methionine methylester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninecyclohexyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine benzylester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine ethylester

N- 1-(Sarcosyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

N- 1-(N,N-Dimethylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine(2-pyridylmethyl) ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine(1-glyceryl) ester

N-1-L-Prolylpyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(L-Prolyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(1-Morpholinoacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(1-Morpholinoacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(4-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(4-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(3-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(3-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(2-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(2-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(4-Pyridyl(N-methyl)glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(4-Pyridyl(N-methyl)glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N- 1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alanine

N- 1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninemethyl ester

N- 1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alanine

N- 1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninemethyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninecyclohexyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(N-methyl)glutamine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(N-methyl)glutaminemethyl ester

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-methylcarbonylamino)alanine

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-methylcarbonylamino)alaninemethyl ester

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-methylsulfonylamino)alanine

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-methylsulfonylamino)alaninemethyl ester

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-propionylamino)alanine

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-propionylamino)alaninemethyl ester

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-pyrrolidinon-1-ylamino)alanine

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-pyrrolidinon-1-ylamino)alaninemethyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(3-methoxybenzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(3-methoxybenzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(3-methoxybenzyl)glycyl-methionine

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(3-methoxybenzyl)glycyl-methioninemethyl ester

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(3-cyanobenzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(3-cyanobenzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(4-cyanobenzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methioninemethyl ester

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methionine

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methylbenzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methylbenzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-trifluoromethylbenzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-trifluoromethylbenzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylsulfonyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylsulfonyl)glycyl-methioninemethyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine4-N-methylpiperidinyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetert-butyl ester

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine 3-pentylester

N- 1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionineisopropyl ester

N-1-(1H-Imidazol-4-ylpropionyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester

N-1-(1H-Imidazol-4-ylpropionyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine

or the pharmaceutically acceptable salts thereof.

Representative compounds of the invention are:

N-1-(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycylmethionine##STR19## N-1-(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester ##STR20## N-1-(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester ##STR21## N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionin##STR22## N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester ##STR23## N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester ##STR24## N-1-(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine##STR25## N-1-(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester ##STR26## 2(S)-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyloxyl!-3-phenylpropionyl-methioninemethyl ester ##STR27## 2(S)-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyloxy!-3-phenylpropionyl-methionine##STR28## N-1-(Sarcosyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine##STR29## N-1-(Sarcosyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester ##STR30## N-1-(N,N-Dimethylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine##STR31## N-1-(N,N-Dimethylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester ##STR32## N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninemethyl ester ##STR33## N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alanine##STR34## N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninecyclohexyl ester ##STR35## N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alanine##STR36## N-1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester ##STR37## N-1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine##STR38## N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine##STR39## N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester ##STR40## N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester ##STR41## N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine##STR42## N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester ##STR43## N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine##STR44## N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methionine##STR45## N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methioninemethyl ester ##STR46## N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine4-N-methylpiperidinyl ester ##STR47## N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester ##STR48## N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine##STR49## N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionineisopropyl ester ##STR50## or the pharmaceutically acceptable saltsthereof.

In the present invention, the amino acids which are disclosed areidentified both by conventional 3 letter and single letter abbreviationsas indicated below:

    ______________________________________    Alanine            Ala    A    Arginine           Arg    R    Asparagine         Asn    N    Aspartic acid      Asp    D    Asparagine or      Asx    B    Aspartic acid    Cysteine           Cys    C    Glutamine          Gln    Q    Glutamic acid      Glu    E    Glutamine or       Glx    Z    Glutamic acid    Glycine            Gly    G    Histidine          His    H    Isoleucine         Ile    I    Leucine            Leu    L    Lysine             Lys    K    Methionine         Met    M    Phenylalanine      Phe    F    Proline            Pro    P    Serine             Ser    S    Threonine          Thr    T    Tryptophan         Trp    W    Tyrosine           Tyr    Y    Valine             Val    V    ______________________________________

The compounds of the present invention may have asymmetric centers andoccur as racemates, racemic mixtures, and as individual diastereomers,with all possible isomers, including optical isomers, being included inthe present invention. Unless otherwise specified, named amino acids areunderstood to have the natural "L" stereoconfiguration

As used herein, "alkyl" is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms.

As used herein, "cycloalkyl" is intended to include non-aromatic cyclichydrocarbon groups having the specified number of carbon atoms. Examplesof cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like.

"Alkenyl" groups include those groups having the specified number ofcarbon atoms and having one or several double bonds. Examples of alkenylgroups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl,2-butenyl, 2-methyl-2-butenyl, isoprenyl, farnesyl, geranyl,geranylgeranyl and the like.

As used herein, "aryl" is intended to include any stable monocyclic,bicyclic or tricyclic carbon ring(s) of up to 7 members in each ring,wherein at least one ring is aromatic. Examples of aryl groups includephenyl, naphthyl, anthracenyl, biphenyl, tetrahydronaphthyl, indanyl,phenanthrenyl and the like.

The term heterocycle or heterocyclic, as used herein, represents astable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclicor stable 11-15 membered tricyclic heterocycle ring which is eithersaturated or unsaturated, and which consists of carbon atoms and fromone to four heteroatoms selected from the group consisting of N, O, andS, and including any bicyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The heterocyclic ring maybe attached at any heteroatom or carbon atom which results in thecreation of a stable structure. Examples of such heterocyclic elementsinclude, but are not limited to, azepinyl, benzimidazolyl,benzisoxazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl,benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl,cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl,dihydrobenzothiopyranyl, dihydrobenzothiopyranyl sulfone, furyl,imidazolidinyl, imidazolinyl, imidazolyl, indolinyl, indolyl,isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide,pyridonyl, pyrazinyl, pyrazolidinyl, pyrazolyl, pyrimidinyl,pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolinyl N-oxide,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl, and thienyl.Preferably, heterocycle is selected from imidazolyl, 2-oxopyrrolidinyl,piperidyl, pyridyl and pyrrolidinyl.

As used herein, the terms "substituted aryl", "substituted heterocycle"and "substituted cycloalkyl" are intended to include the cyclic groupwhich is substituted with 1 or 2 substitutents selected from the groupwhich includes but is not limited to F, Cl, Br, CF₃, NH₂, N(C₁ -C₆alkyl)₂, NO₂, CN, (C₁ -C₆ alkyl)O--, --OH, (C₁ -C₆ alkyl)S(O)_(m) --,(C₁ -C₆ alkyl)C(O)NH--, H₂ N--C(NH)--, (C₁ -C₆ alkyl)C(O)--, (C₁ -C₆alkyl)OC(O)--, N₃, (C₁ -C₆ alkyl)OC(O)NH-- and C₁ -C₂₀ alkyl.

The following structure: ##STR51## represents a cyclic amine moietyhaving 5 or 6 members in the ring, such a cyclic amine which may beoptionally fused to a phenyl or cyclohexyl ring. Examples of such acyclic amine moiety include, but are not limited to, the followingspecific structures: ##STR52## It is also understood that substitutionon the cyclic amine moiety by R^(2a) and R^(2b) may be on differentcarbon atoms or on the same carbon atom.

When R³ and R⁴ are combined to form --(CH₂)_(s) --, cyclic moieties areformed. Examples of such cyclic moieties include, but are not limitedto: ##STR53##

When R^(5a) and R^(5b) are combined to form --(CH₂)_(s) --, cyclicmoieties as described hereinabove for R³ and R⁴ are formed. In addition,such cyclic moieties may optionally include a heteroatom(s). Examples ofsuch heteroatom-containing cyclic moieties include, but are not limitedto: ##STR54##

Preferably, R^(1a) and R^(1b) are independently selected from: hydrogen,--N(R¹⁰)₂, R¹⁰ C(O)NR¹⁰ -- or C₁ -C₆ alkyl unsubstituted or substitutedby --N(R¹⁰)₂, R¹⁰ O-- or R¹⁰ C(O)NR¹⁰ --.

Preferably, R^(2a) and R^(2b) are independently selected from: hydrogenand C₁ -C₆ alkyl.

Preferably, R³ and R⁴ are independently selected from: a side chain of anaturally occurring amino acid and C₁ -C₆ alkyl unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl.

Preferably, R^(5a) and R^(5b) are independently selected from: a sidechain of a naturally occurring amino acid, methionine sulfoxide,methionine sulfone and unsubstituted or substituted C₁ -C₆ alkyl.

Preferably, X--Y is selected from: ##STR55##

Preferably, R^(7b) is C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted aryl group.

Preferably, R⁸ is selected from: hydrogen, perfluoroalkyl, F, Cl, Br,R¹⁰ O--, R¹¹ S(O)_(m) --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ -- and C₁ -C₆ alkyl.

Preferably, R⁹ is hydrogen.

Preferably, R¹⁰ is selected from H, C₁ -C₆ alkyl and benzyl.

Preferably, A¹ and A² are independently selected from: a bond,--C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)-- and--N(R¹⁰)S(O)₂ --.

Preferably, V is selected from hydrogen, heterocycle and aryl.

Preferably, n, p and r are independently 0, 1, or 2.

Preferably t is 3.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed, e.g., from non-toxic inorganic or organic acids.For example, such conventional non-toxic salts include those derivedfrom inorganic acids such as hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like: and the salts prepared fromorganic acids such as acetic, propionic, succinic, glycolic, stearic,lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenyl-acetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like.

It is intended that the definition of any substituent or variable (e.g.,R¹⁰, Z, n, etc.) at a particular location in a molecule be independentof its definitions elsewhere in that molecule. Thus, --N(R¹⁰)₂represents --NHH, --NHCH₃, --NHC₂ H₅, etc. It is understood thatsubstituents and substitution patterns on the compounds of the instantinvention can be selected by one of ordinary skill in the art to providecompounds that are chemically stable and that can be readily synthesizedby techniques known in the art as well as those methods set forth below.

The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic moiety by conventional chemical methods. Generally, the salts areprepared by reacting the free base with stoichiometric amounts or withan excess of the desired salt-forming inorganic or organic acid in asuitable solvent or various combinations of solvents.

The compounds of the invention can be synthesized from their constituentamino acids by conventional peptide synthesis techniques, and theadditional methods described below. Standard methods of peptidesynthesis are disclosed, for example, in the following works: Schroederet al., "The Peptides", Vol. I, Academic Press 1965, or Bodanszky etal., "Peptide Synthesis", Interscience Publishers, 1966, or McOmie (ed.)"Protective Groups in Organic Chemistry", Plenum Press, 1973, or Baranyet al., "The Peptides: Analysis, Synthesis, Biology" 2, Chapter 1,Academic Press, 1980, or Stewart et al., "Solid Phase PeptideSynthesis", Second Edition, Pierce Chemical Company, 1984. Also usefulin exemplifying syntheses of specific unnatural amino acid residues areEuropean Pat. Appl. No. 0 350 163 A2 (particularly page 51-52) and J. E.Baldwin et al. Tetrahedron, 50:5049-5066 (1994). With regards to thesynthesis of instant compounds containing a (β-acetylamino)alanineresidue at the C-terminus, use of the commercially available N.sub.α-Z-L-2,3-diaminopropionic acid (Fluka) as a starting material ispreferred. The teachings of these works are hereby incorporated byreference.

Abbreviations used in the description of the chemistry and in theExamples that follow are:

    ______________________________________    Ac.sub.2 O              Acetic anhydride;    Boc       t-Butoxycarbonyl;    DBU       1,8-diazabicyclo 5.4.0!undec-7-ene;    DMAP      4-Dimethylaminopyridine;    DME       1,2-Dimethoxyethane;    DMF       Dimethylformamide;    EDC       1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide-              hydrochloride;    HOBT      1-Hydroxybenzotriazole hydrate;    Et.sub.3 N              Triethylamine;    EtOAc     Ethyl acetate;    FAB       Fast atom bombardment;    HOOBT     3-Hydroxy-1,2,2-benzotriazin-4(3H)-one;    HPLC      High-performance liquid chromatography;    MCPBA     m-Chloroperoxybenzoic acid;    MsCl      Methanesulfonyl chloride;    NaHMDS    Sodium bis(trimethylsilyl)amide;    Py        Pyridine;    TFA       Trifluoroacetic acid;    THF       Tetrahydrofuran.    ______________________________________

Compounds of this invention are prepared by employing the reactionsshown in the following Reaction Schemes A-J, in addition to otherstandard manipulations such as ester hydrolysis, cleavage of protectinggroups, etc., as may be known in the literature or exemplified in theexperimental procedures. Some key bond-forming and peptide modifyingreactions are:

Reaction A Amide bond formation and protecting group cleavage usingstandard solution or solid phase methodologies.

Reaction B Preparation of a reduced peptide subunit by 1 reductivealkylation of an amine by an aldehyde using sodium cyanoborohydride orother reducing agents.

Reaction C Alkylation of a reduced peptide subunit with an alkyl oraralkyl halide or, alternatively, reductive alkylation of a reducedpeptide subunit with an aldehyde using sodium cyanoborohydride or otherreducing agents.

Reaction D Peptide bond formation and protecting group cleavage usingstandard solution or solid phase methodologies.

Reaction E Preparation of a reduced subunit by borane reduction of theamide moiety.

Reaction Schemes A-E illustrate bond-forming and peptide modifyingreactions incorporating acyclic peptide units. It is well understoodthat such reactions are equally useful when the --NHC(R^(A))-- moiety ofthe reagents and compounds illustrated is replaced with the followingmoiety: ##STR56## These reactions may be employed in a linear sequenceto provide the compounds of the invention or they may be used tosynthesize fragments which are subsequently joined by the alkylationreactions described in the Reaction Schemes. ##STR57## where R^(A) andR^(B) are R³, R⁴, R^(5a) or R^(5b) as previously defined; R^(C) is R⁶ aspreviously defined or a carboxylic acid protecting group; X^(L) is aleaving group, e.g., Br⁻, I⁻ or MsO⁻ ; and R^(y) is defined such thatR^(7b) is generated by the reductive alkylation process.

Certain compounds of this invention wherein X--Y is an ethenylene orethylene unit are prepared by employing the reaction sequences shown inReaction Schemes F and G. Reaction Scheme F outlines the preparation ofthe alkene isosteres utilizing standard manipulations such as Weinrebamide formation, Grignard reaction, acetylation, ozonolysis, Wittigreaction, ester hydrolysis, peptide coupling reaction, mesylation,cleavage of peptide protecting groups, reductive alkylation, etc., asmay be known in the literature or exemplified in the ExperimentalProcedure. For simplicity, substituents R^(2a) and R^(2b) on the cyclicamine moiety are not shown. It is, however, understood that thereactions illustrated are also applicable to appropriately substitutedcyclic amine compounds. The key reactions are: stereoselective reductionof the Boc-amino-enone to the corresponding syn amino-alcohol (Scheme F,Step B, Part 1), and stereospecific boron triflouride or zinc chlorideactivated organo-magnesio, organo-lithio, or organo-zinc copper(1)cyanide S_(N) 2' displacement reaction (Scheme F, Step G). Through theuse of optically pure N-Boc amino acids as starting material and thesetwo key reactions, the stereo-chemistry of the final products is welldefined. In Step H of Scheme F, the amino terminus sidechain, designatedR^(x) is incorporated using coupling reaction A and R^(x) COOH; thealkylation reaction C using R^(x) CHO and a reducing agent; oralkylation reaction C using R^(x) CH₂ X^(L). Such reactions as describedin Step H are described in more detail in Reaction Schemes J-Xhereinbelow.

The alkane analogs are prepared in a similar manner by including anadditional catalytic hydrogenation step as outlined in Reaction SchemeG. ##STR58##

The oxa isostere compounds of this invention are prepared according tothe route outlined in Scheme H. An aminoalcohol 1 is acylated withalpha-chloroacetyl chloride in the presence of trialkylamines to yieldamide 2. Subsequent reaction of 2 with a deprotonation reagent (e.g.,sodium hydride or potassium t-butoxide) in an ethereal solvent such asTHF provides morpholinone 3. Alkylation of 3 with R³ X^(L), where X^(L)is a leaving group such as Br⁻, I⁻ or Cl⁻ in THF/DME(1,2-dimethoxyethane) in the presence of a suitable base, preferablyNaHMDS sodium bis(trimethylsilyl)amide!, affords 4, which is retreatedwith NaHMDS followed by either protonation or the addition of an alkylhalide R⁴ X to give 5a or 5b, respectively, as a enantiomeric mixture.Alternatively, 5a can be prepared from 3 via an aldol condensationapproach. Namely, deprotonation of 3 with NaHMDS followed by theaddition of a carbonyl compound R^(y) R^(z) CO gives the adduct 6.Dehydration of 6 can be effected by mesylation and subsequentelimination catalyzed by DBU (1,8-diazabicyclo 5.4.0!undec-7-ene) or thedirect treatment of 6 with phosphorus oxychloride in pyridine to giveolefin 7. Then, catalytic hydrogenation of 7 yields 5a (wherein--CHR^(y) R^(z) constitutes R³). Direct hydrolysis of 5 with lithiumhydrogen peroxide in aqueous THF, or aqueous HCl, produces acid 8a.Compound 8a is then derivatized with BOC--ON or BOC anhydride to give8b. The peptide coupling of acid 8b with either an alpha-aminolactone(e.g., homoserine lactone, etc.) or the ester of an amino acid iscarried out under the conditions exemplified in the previously describedreferences to yield derivative 9. Treatment of 9 with gaseous hydrogenchloride gives 10, which undergoes further elaboration as described inReaction Schemes J-hereinbelow.

An alternative method for the preparation of the prolyl oxa isostere(compounds 23 and 24) is shown in Scheme H-1. Referring to Scheme H-1,the aminoalcohol 1 is protected with trifluoroacetic anhydride and theblocked compound 15 treated with diphenyl disulfide in the presence oftributylphosphine to provide the thioether 16. Chlorination of compound16 provides compound 17 which can be reacted with the appropriatecarboxylic acid alcohol in the presence of silver perchlorate and tin(II) chloride, to afford the mixed acetal 18. Removal of thephenylmercapto moiety with Raney nickel provides compound 19. Compound19 is doubly deprotected, then selectively BOC protected to provide theacid 20, which undergoes the steps previously described forincorporating terminal amino acid. Still another alternative method forthe preparation of the prolyl oxa isostere (compounds 23 and 24 ) isdescribed in the literature Ruth E. TenBrink, J. Org. Chem., 52, 418-422(1987)!. ##STR59##

The thia, oxothia and dioxothia isostere compounds of this invention areprepared in accordance to the route depicted in Scheme I. Aminoalcohol 1is derivatized with BOC₂ O to give 25. Mesylation of 25 followed byreaction with methyl alpha-mercaptoacetate in the presence of cesiumcarbonate gives sulfide 26. Removal of the BOC group in 26 with TFAfollowed by neutralization with di-isopropylethylamine leads to lactam27. Sequential alkylation of 27 with the alkyl halides R³ X and R⁴ X inTHF/DME using NaHDMS as the deprotonation reagent produces 28.Hydrolysis of 28 in hydrochloride to yield 29a, which is derivatizedwith Boc anhydride to yield 29b. The coupling of 29b with analpha-aminolactone (e.g., homoserine lactone, etc.) or the ester of anamino acid is carried out under conventional conditions as exemplifiedin the previously described references to afford 30. Sulfide 30 isreadily oxidized to sulfone 31 by the use of MCPBA(m-chloroperoxybenzoic acid). The N--BOC group of either 30 or 31 isreadily removed by treatment with gaseous hydrogen chloride. ##STR60##

Reaction Schemes J-R illustrate reactions wherein thenon-sulfhydryl-containing moiety at the N-terminus of the compounds ofthe instant invention is attached to the fully elaborated cyclic aminopeptide unit, prepared as described in Reaction Schemes A-I. It isunderstood that the reactions illustrated may also be performed on asimple cyclic amino acid, which may then be further elaborated utilizingreactions described in Reaction Schemes A-I to provide the instantcompounds.

The intermediates whose synthesis are illustrated in Reaction SchemesA-I can be reductively alkylated with a variety of aldehydes, such as V,as shown in Reaction Scheme J. The aldehydes can be prepared by standardprocedures, such as that described by O. P. Goel, U. Krolls, M. Stierand S. Kesten in Organic Syntheses, 1988, 67, 69-75, from theappropriate amino acid (Reaction Scheme F). The reductive alkylation canbe accomplished at pH 5-7 with a variety of reducing agents, such assodium triacetoxyborohydride or sodium cyanoborohydride in a solventsuch as dichloroethane, methanol or dimethylformamide. The product VIcan be deprotected with trifluoroacetic acid in methylene chloride togive the final compounds VII. The final product VII is isolated in thesalt form, for example, as a trifluoroacetate, hydrochloride or acetatesalt, among others. The product diamine VII can further be selectivelyprotected to obtain VIII, which can subsequently be reductivelyalkylated with a second aldehyde to obtain IX. Removal of the protectinggroup, and conversion to cyclized products such as the dihydroimidazoleXI can be accomplished by literature procedures.

Alternatively, the protected cyclic aminopeptidyl intermediate can bereductively alkylated with other aldehydes such as1-trityl-4-carboxaldehyde or 1-trityl-4-imidazolylacetaldehyde, to giveproducts such as XII (Reaction Scheme K). The trityl protecting groupcan be removed from XII to give XIII, or alternatively, XII can first betreated with an alkyl halide then subsequently deprotected to give thealkylated imidazole XIV. Alternatively, the dipeptidyl analogintermediate can be acylated or sulfonylated by standard techniques.

The imidazole acetic acid XV can be converted to the protected acetateXVII by standard procedures, and XVII can be first reacted with an alkylhalide, then treated with refluxing methanol to provide theregiospecifically alkylated imidazole acetic acid ester XVIII.Hydrolysis and reaction with the protected dipeptidyl analogintermediate in the presence of condensing reagents such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) leads to acylatedproducts such as XIX.

If the protected dipeptidyl analog intermediate is reductively alkylatedwith an aldehyde which also has a protected hydroxyl group, such as XXin Reaction Scheme N, the protecting groups can be subsequently removedto unmask the hydroxyl group (Reaction Schemes N, P). The alcohol can beoxidized under standard conditions to e.g. an aldehyde, which can thenbe reacted with a variety of organometallic reagents such as Grignardreagents, to obtain secondary alcohols such as XXIV. In addition, thefully deprotected amino alcohol XXV can be reductively alkylated (underconditions described previously) with a variety of aldehydes to obtainsecondary amines, such as XXVI (Reaction Scheme P), or tertiary amines.

The Boc protected amino alcohol XXII can also be utilized to synthesize2-aziridinylmethylpiperazines such as XXVII (Reaction Scheme Q).Treating XXII with 1,1'-sulfonyldiimidazole and sodium hydride in asolvent such as dimethylformamide led to the formation of aziridineXXVII. The aziridine may be reacted in the presence of a nucleophile,such as a thiol, in the presence of base to yield the ring-openedproduct XXVIII.

In addition, the protected dipeptidyl analog intermediate can be reactedwith aldehydes derived from amino acids such as O-alkylated tyrosines,according to standard procedures, to obtain compounds such as XXXIV, asshown in Reaction Scheme R. When R' is an aryl group, XXXIV can first behydrogenated to unmask the phenol, and the amine group deprotected withacid to produce XXXV. Alternatively, the amine protecting group in XXXIVcan be removed, and O-alkylated phenolic amines such as XXXVI produced.##STR61##

The compounds of this invention inhibit Ras farnesyl transferase whichcatalyzes the first step in the post-translational processing of Ras andthe biosynthesis of functional Ras protein. These compounds are usefulas pharmaceutical agents for mammals, especially for humans. Thesecompounds may be administered to patients for use in the treatment ofcancer. Examples of the type of cancer which may be treated with thecompounds of this invention include, but are not limited to, colorectalcarcinoma, exocrine pancreatic carcinoma, and myeloid leukemias.

The compounds of this invention are also useful for inhibitingproliferative diseases, both benign and malignant, wherein Ras proteinsare aberrantly activated as a result of oncogenic mutation in othergenes (i.e., the Ras gene itself is not activated by mutation to anoncogenic form) with said inhibition being accomplished by theadministration of an effective amount of the compounds of the inventionto a mammal in need of such treatment. For example, the benignproliferative disorder neurofibromatosis, or tumors in which the Ras isactivated due to mutation or overexpression of tyrosine kinase oncogenes(e.g., neu, src, abl, lck, and fyn) may be inhibited by the compounds ofthis invention. Furthermore, arteriosclerosis and diabetic disturbanceof blood vessels may be prevented or treated by use of the instantcompounds to inhibit proliferation of vascular smooth muscle cells.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

For oral use of a chemotherapeutic compound according to this invention,the selected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch, and lubricating agents, such as magnesiumstearate, are commonly added. For oral administration in capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring agents may be added. For intramuscular,intraperitoneal, subcutaneous and intravenous use, sterile solutions ofthe active ingredient are usually prepared, and the pH of the solutionsshould be suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled in order to render thepreparation isotonic.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of cancer, comprising the administration of atherapeutically effective amount of the compounds of this invention,with or without pharmaceutically acceptable carriers or diluents.Suitable compositions of this invention include aqueous solutionscomprising compounds of this invention and pharmacologically acceptablecarriers, e.g., saline, at a pH level, e.g., 7.4. The solutions may beintroduced into a patient's intramuscular bloodstream by local bolusinjection.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment for cancer. Administrationoccurs in an amount between about 0.1 mg/kg of body weight to about 20mg/kg of body weight per day, preferably of between 0.5 mg/kg of bodyweight to about 10 mg/kg of body weight per day.

The compounds of the instant invention are also useful as a component inan assay to rapidly determine the presence and quantity offarnesyl-protein transferase (FPTase) in a composition. Thus thecomposition to be tested may be divided and the two portions contactedwith mixtures which comprise a known substrate of FPTase (for example atetrapeptide having a cysteine at the amine terminus) and farnesylpyrophosphate and, in one of the mixtures, a compound of the instantinvention. After the assay mixtures are incubated for an sufficientperiod of time, well known in the art, to allow the FPTase tofarnesylate the substrate, the chemical content of the assay mixturesmay be determined by well known immunological, radiochemical orchromatographic techniques. Because the compounds of the instantinvention are selective inhibitors of FPTase, absence or quantitativereduction of the amount of substrate in the assay mixture without thecompound of the instant invention relative to the presence of theunchanged substrate in the assay containing the instant compound isindicative of the presence of FPTase in the composition to be tested.

It would be readily apparent to one of ordinary skill in the art thatsuch an assay as described above would be useful in identifying tissuesamples which contain farnesyl-protein transferase and quantitating theenzyme. Thus, potent inhibitor compounds of the instant invention may beused in an active site titration assay to determine the quantity ofenzyme in the sample. A series of samples composed of aliquots of atissue extract containing an unknown amount of farnesyl-proteintransferase, an excess amount of a known substrate of FPTase (forexample a tetrapeptide having a cysteine at the amine terminus) andfarnesyl pyrophosphate are incubated for an appropriate period of timein the presence of varying concentrations of a compound of the instantinvention. The concentration of a sufficiently potent inhibitor (i.e.,one that has a Ki substantially smaller than the concentration of enzymein the assay vessel) required to inhibit the enzymatic activity of thesample by 50% is approximately equal to half of the concentration of theenzyme in that particular sample.

EXAMPLES

Examples provided are intended to assist in a further understanding ofthe invention. Particular materials employed, species and conditions areintended to be further illustrative of the invention and not limitativeof the reasonable scope thereof.

The standard workup referred to in the examples refers to solventextraction and washing the organic solution with 10% citric acid, 10%sodium bicarbonate and brine as appropriate. Solutions were dried oversodium sulfate and evaporated in vacuo on a rotary evaporator.

Example 1 Preparation of N-1-(4-imidazoleacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

Step A: Preparation of N-(t-Butoxycarbonylpyrrolidin-2(S)-ylmethyl)glycine methyl ester

N-(t-Butoxycarbonyl)-L-prolinal (9.16 g, 0.046 mol) and glycine methylester hydrochloride salt (5.78 g, 0.046 mol) were dissolved in MeOH (180mL) at 0° C. under nitrogen, treated with sodium cyanoborohydride (4.34g, 0.069 mol), and stirred for 18 h. The mixture was concentrated, andthe residue was partitioned between EtOAc (100 mL) and satd aq NaHCO₃soln (100 mL). The basic layer was washed with EtOAc (2×50 mL), theorganics combined, washed with brine, and dried over Na₂ SO₄. Filtrationand concentration to dryness gave the title compound as a pale yellowoil. ¹ H NMR (CDCl₃) δ3.7-3.9 (m, 1H), 3.72 (s, 3H), 3.43 (s, 2H), 3.33(s, 2H), 2.7-2.9 (m, 1H), 2.5-2.65 (m, 1H), 1.75-2.0 (m, 4H), 1.47 (s,9H).

Step B: Preparation ofN-(t-Butoxycarbonylpyrrolidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)glycine methyl ester

N-(t-Butoxycarbonylpyrrolidin-(2S)-ylmethyl) glycine methyl ester (3.0g, 0.011 mol) was dissolved in 1,2-dichloroethane (100 ml) and 3Amolecular sieves (3 g) were added followed by 1-naphthaldehyde (1.63 ml,0.012 mol) and sodium triacetoxyborohydride (4.64 g, 0.022 mol). Themixture was stirred at ambient temperature for 5 h, and filtered throughglass fiber paper and concentrated. The residue was partitioned betweenEtOAc and sat. NaHCO₃ (100 ml/25 ml). The aqueous layer was washed withEtOAc (3×50 ml). The organic layers were combined, dried with Na₂ SO₄,filtered, and concentrated to give 5.2 g of crude product which waspurified by chromatography (silica gel 1:6 EtOAc/hexane) to give thetitle compound. ¹ H NMR (CDCl₃) δ8.24-8.4 (m, 1H), 7.7-7.9 (m, 2H),7.35-7.5 (m, 4H), 4.43 (d, 1H, J=12 Hz), 3.8-4.1 (m, 2H). 3.68 (s, 3H),3.15-3.5 (m, 4H), 2.94 (t, 1H, J=12 Hz), 2.44 (t, 1H, J=11 Hz), 1.7-1.8(m, 2H), 1.5-1.7 (m, 2H), 1.47 (s, 9H).

Step C: Preparation ofN-(t-Butoxycarbonylpyrrolidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)glycine

N-(t-Butoxycarbonylpyrrolidin-(2S)-ylmethyl)-N-(1-naphthylmethyl)glycinemethyl ester (2.91 g, 7.10 mmol) was dissolved in MeOH (60 ml) and 1NNaOH (21.3 ml, 21.3 mmol) was added. The mixture was stirred at ambienttemperature for 5 h and concentrated. The resulting residue wasdissolved in H₂ O (25 ml) and neutralized with 1N HCl (21.3 ml). Theaqueous layer was washed with EtOAc (3×50 ml). The organic layers werecombined, dried with Na₂ SO₄, filtered, and concentrated to give theproduct. ¹ H NMR (CD₃ OD); δ8.57 (d, 1H, J=9 Hz), 7.5-8.0 (m, 6H), 5.13(d, 1H, J=12 Hz), 4.71 (d, 1H, J=12 Hz), 4.05-4.15 (m, 1H), 3.71 (ABq,2H), 3.2-3.4 (m, 3H), 3.0-3.1 (m, 1H), 2.0-2.1 (m, 1H), 1.6-1.75 (m,2H), 1.5-1.6 (m, 1H), 1.30 (s, 9H).

Step D: Preparation ofN-(t-Butoxycarbonylpyrrolidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)glycine-methioninemethyl ester

N-(t-Butoxycarbonylpyrrolidin(-2S)-ylmethyl)-N-(1-naphthylmethyl)glycine (1.44 g, 3.6 mmol), dissolved in CH₂ Cl₂ (30 mL), was treatedwith HOBT (0.581 g, 4.3 mmol), EDC (0.831 g, 4.3 mmol), and methioninemethyl ester hydrochloride (0.859 g, 4.3 mmol). The pH was adjusted to7.5 with Et₃ N (1.1 mL, 7.9 mmol) and the mixture was stirred at ambienttemperature for 18 h. The mixture was concentrated, and the residue waspartitioned between CH₂ Cl₂ (50 mL) and saturated NaHCO₃ solution (25mL). The aqueous layer was extracted with CH₂ Cl₂ (2×50 mL). The organiclayers were combined, washed with brine (1×25 mL), dried (Na₂ SO₄),filtered, and concentrated to give 2.0 g of crude product which waspurified by chromatography (silica gel eluting with 1:3 to 1:1 ethylacetate in hexane) to give pure product. ¹ H NMR (CDCl₃); δ8.22 (d, 1H,J=9 Hz), 7.8-7.95 (m, 2H), 7.4-7.6 (m, 4H), 4.54 (d, 1H, J=16 Hz),4.3-4.5 (m, 2H), 4.07-4.15 (m, 1H), 3.7-3.9 (m, 2H), 3.68 (s, 3H),3.25-3.4 (m, 3H), 3.04-3.15 (m, 1H), 2.85-3.0 (m, 1H), 2.4-2.5 (m, 1H),1.89 (s, 3H). 1.53-2.5 (m, 5H), 1.48 (s. 9H), 1.2-1.45 (m, 2H).

Step E: Preparation ofN-(pyrrolidin-(2S)-ylmethyl)-N-(1-naphthylmethyl)-glycyl-methioninemethyl ester hydrochloride

N-(t-Butoxycarbonylpyrrolidin-(2S)-ylmethyl)-N-(1-naphthylmethyl)-glycyl-methioninemethyl ester (1.5 g, 2.76 mmol) was dissolved in EtOAc (50 mL) andcooled to 0° C. HCl was bubbled through the mixture until TLC (95:5 CH₂Cl₂ :MeOH) indicated complete reaction. Argon was bubbled through themixture to remove excess HCl and the mixture was then concentrated togive the title compound. ¹ H NMR (CD₃ OD) δ8.23 (d, 1H, J=8 Hz),7.9-7.95 (m, 2H), 7.45-7.65 (m, 4H), 4.4-4.6 (m, 4H). 3.7-3.8 (m, 1H),3.71 (s, 3H), 3.5-3.7 (m, 2H), 3.12-3.28 (m, 2H), 2.9-3.05 (m, 1H),2.35-2.5 (m, 2H), 1.93-2.15 (m, 4H), 2.02 (s, 3H), 1.77-1.89 (m, 1H),1.6-1.7 (m, 1H).

Anal. Calcd for C₂₄ H₃₃ N₃ O₃ S.2 HCl.0.5 H₂ O: C, 54.85; H, 6.90; N,8.00. Found: C, 54.77; H, 6.72; N, 7.79.

Step F: Preparation of N-1-(4-imidazoleacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-(pyrrolidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)-glycyl-methioninemethyl ester hydrochloride (0.200 g, 0.387 mmol), imidazoleacetic acidhydrochloride (0.094 g, 0.581 mmol), hydroxybenzotriazole hydrate (0.086g, 0.639 mmol), EDC hydrochloride (0.134 g, 0.697 mmol) and TEA (0.340mL, 2.44 mmol) were dissolved in dry DMF (4 mL) and stirred under Ar for3 h. The mixture was concentrated in vacuo and the residue taken up inaq satd NaHCO₃ soln and extracted with EtOAc (2×40 mL). The organicswere washed with H₂ O and brine, dried over MgSO₄, filtered and thesolvent removed in vacuo to give an oil which was chromatographed onsilica gel (5:95 MeOH:CH₂ Cl₂) to give the title compound. ¹ H NMR (CD₃OD) δ8.32 (d, 1H, J=8 Hz), 7.90 (d, 1H, J=8 Hz), 7.83 (d, 1H, J=8 Hz),7.39 -7.62 (m, 5H), 6.92 (br s, 1H), 4.34-4.52 (m, 3H), 3.94 (d, 1H,J=13 Hz), 3.59-3.78 (m, 2H), 3.67 (s, 3H), 3.21-3.56 (m, 6H), 2.93 (dd,1H, J=4, 13 Hz), 2.51 (dd, 1H, J=9, 13 Hz), 2.02-2.14 (m, 1H), 1.68-2.02(m, 6H), 1.92 (s, 3H), 1.39-1.52 (m, 1H).

Anal. Calcd for C₂₉ H₃₇ N₅ O₄ S.0.4 CH₂ Cl₂ : C, 60.29; H, 6.51; N,11.93. Found: C, 60.39; H, 6.57; N, 11.99.

Using the methods outlined in Example 1, the following esters wereprepared:

N- 1-(2(S),3-Diaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester tris hydrochloride salt

Anal. Calcd for C₂₇ H₃₉ N₅ O₄ S.3.95 HCl.0.95 H₂ O: C, 46.94; H, 6.54;N, 10.14; Found: C, 46.84; H, 6.42; N, 10.20.

N-1-(2(S)-Amino-3-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester bis hydrochloride

Anal. Calcd for C₃₅ H₄₅ N₅ O₆ S.2.8 HCl: C, 54.89; H, 6.29; N, 9.14;Found: C, 54.95; H, 6.35; N, 8.84.

N- 1-(3-Amino-2(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester bis trifluoroacetate

FAB MS 664 (M+1).

N-1-(L-Glutaminyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester bis trifluoroacetate

Anal. Calcd for C₂₉ H₄₁ N₅ O₅ S.2.85 CF₃ CO₂ H: C, 46.48; H, 4.93; N,7.81; Found: C, 46.40; H, 5.29; N, 8.16.

N-1-L-Histidinylpyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester tris trifluoroacetate

FAB MS 581 (M+1).

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester bis hydrochloride

Anal. Calcd for C₂₆ H₃₆ N₄ O₄ S.2 HCl.0.95 H₂ O: C, 52.87; H, 6.81; N,9.48; Found: C, 52.63; H, 6.64; N, 9.26.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine sulfonemethyl ester trifluoroacetate

Anal. Calcd for C₂₆ H₃₆ N₄ O₆ S.2.3 CF₃ CO₂ H.0.3 H₂ O: C, 45.92; H,4.90; N, 7.00; Found: C, 45.91; H, 4.91; N, 7.29.

N- 1-(β-Alanyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester bis hydrochloride

Anal. Calcd for C₂₇ H₃₈ N₄ O₄ S.2 HCl.0.9 H₂ O: C, 53.71; H, 6.98; N,9.28; Found: C, 53.69; H, 6.74; N, 9.19.

N- 1-(Sarcosyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester bis hydrochloride

Anal. Calcd for C₂₇ H₃₈ N₄ O₄ S.2 HCl.1.6 H₂ O: C, 52.61; H, 7.06; N,9.09; Found: C, 52.61; H, 6.74; N, 8.79.

N- 1-(N,N-Dimethylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester bis hydrochloride

Anal. Calcd for C₂₈ H₄₀ N₄ O₄ S.2 HCl.0.85 H₂ O: C, 54.51; H, 7.14; N,9.08; Found: C, 54.50; H, 7.10; N, 8.71.

N-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester trifluoroacetate

Anal. Calcd for C₃₇ H₄₂ N₆ O₄ S.2.9 CF₃ CO₂ H.0.45 H₂ O: C, 51.12; H,4.59; N, 8.36; Found: C,51.11; H, 4.60; N, 8.52.

N-1-(Seryl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester trifluoroacetate

Anal. Calcd for C₂₇ H₃₈ N₄ O₅ S.2.95 CF₃ CO₂ H.0.8 H₂ O: C, 44.83; H,4.87; N, 6.36; Found: C, 44.82; H, 4.67; N, 6.61.

N- 1-(D-Alanyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester hydrochloride

Anal. Calcd for C₂₇ H₃₈ N₄ O₄ S.2.95 HCl.0.25 EtOAc: C, 52.20; H, 6.72;N, 8.70; Found: C, 52.10H, 6.60; N, 8.70.

N-1-(1H-imidazol-4-carbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₈ H₃₅ N₅ O₄ S.0.95 H₂ O: C, 60.62; H, 6.70; N, 12.62;Found: C, 60.24; H, 6.42; N, 12.23.

N- 1-(Isoasparagyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester trifluoro acetate

Anal. Calcd for C₂₈ H₃₉ N₅ O₅ S.2.5 CF₃ CO₂ H.0.3 H₂ O: C, 46.73; H,5.00; N, 8.26; Found: C, 46.71; H, 5.00; N, 8.26.

N- 1-(1H-Imidazol-4-propionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

Anal. Calcd for C₃₀ H₃₉ N₅ O₄ S.0.3 H₂ O: C, 63.09; H, 6.99; N, 12.26;Found: C, 63.05; H, 6.88; N, 12.21.

N- 1-(3-Pyridylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester hydrochloride

Anal. Calcd for C₃₁ H₃₈ N₄ O₄ S.2.65 HCl.0.7 EtOAc: C, 56.30; H, 6.47;N, 7.77; Found: C,56.35; H, 6.44; N, 7.77.

N- 1-(2-Pyridylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

Anal. Calcd for C₃₁ H₃₈ N₄ O₄ S.0.35 CH₂ Cl₂ : C, 63.56; H, 6.58; N,9.46; Found: C,63.63; H, 6.55; N, 9.46.

N- 1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methylester

Anal. Calcd for C₃₁ H₃₉ N₅ O₄ S.0.65 CH₂ Cl₂ : C, 60.06; H, 6.42; N,11.06; Found: C, 60.02; H, 6.52; N, 11.33.

N-1-L-Prolylpyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester bis hydrochloride

Anal. Calcd for C₂₉ H₄₀ N₄ O₄ S.2 HCl.1.5 H₂ O: C, 54.36; H, 7.08; N,8.75; Found: C, 54.50; H, 6.84; N, 8.40.

N-1-(1-morpholinoacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester tris trifluoroacetate

Anal. Calcd for C₃₀ H₄₂ N₄ O₅ S.3.5 CF₃ CO₂ H: C, 45.82; H, 4.73; N,5.78; Found: C, 45.74; H, 5.00; N, 6.02.

N-1-(4-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester trifluoroacetate

Anal. Calcd for C₃₀ H₄₂ N₄ O₄ S.3.2 CF₃ CO₂ H.0.4 H₂ O: C, 47.17; H,5.00; N, 6.05; Found: C, 47.14; H, 5.01; N, 6.19.

N-1-(3-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester tris trifluoroacetate

Anal. Calcd for C₃₀ H₄₂ N₄ O₄ S.3.2 CF₃ CO₂ H.0.8 H₂ O: C, 46.81; H,5.05; N, 6.00; Found: C, 46.81; H, 5.02; N, 6.12.

N-1-(2-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester tris trifluoroacetate

Anal. Calcd for C₃₁ H₃₉ N₅ O₄ S.2.9 CF₃ CO₂ H: C, 48.66; H, 4.65; N, 7.71; Found: C, 48.66; H, 4.65; N, 7.94.

N-1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

Anal. Calcd for C₃₁ H₃₉ N₅ O₄ S.0.65 CH₂ Cl₂ : C, 60.06; H, 6.42; N,11.06; Found: C, 60.02; H, 6.52; N, 11.33.

N-1-(4-Pyridyl(N-methyl)glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

Anal. Calcd for C₃₂ H₄₁ N₅ O₄ S.0.45 CH₂ Cl₂ : C, 61.87; H, 6.70; N,11.12; Found: C, 61.79; H, 6.75; N, 11.44.

Example 2 Preparation of N-1-(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninebis trifluoroacetate salt

N-1-(4-Imidazoleacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester (0.053 g, 0.096 mmol) was dissolved in MeOH (1 mL) withcooling in an ice bath. 1N NaOH (0.384 mL, 0.384 mmol) was added, thebath was removed, and stirred for 2 h. The mixture was cooled in an icebath and treated with 1N HCl (0.384 mL, 0.384 mmol) with stirring. After0.5 h H₂ O (20 mL) was added, and the mixture was extracted with EtOAc(2×20 mL), dried over MgSO₄, filtered, and concentrated to give thetitle compound after chromatography on RP HPLC (0.1% TFA in CH₃ CN/0.1%TFA in H₂ O) and lyophilization. ¹ H NMR (CD₃ OD) δ8.84 (d, 1H, J=8 Hz),8.33 (d, 1H, J=8 Hz), 7.98 (d, 1H, J=8 Hz), 7.94 (d, 1H, J=8 Hz), 7.73(d, 1H, J=7 Hz), 7.63-7.44 (m, 3H), 7.29 (br s, 1H), 4.38-4.56 (m, 3H),3.76-4.05 (m, 4H), 3.55-3.74 (m, 3H), 3.34-3.51 (m, 3H), 2.41-2.50 (m,1H), 2.30-2.41 (m, 1H), 1.70-2.22 (m, 5H), 2.03 (s, 3H). FAB MS 538(M+1).

Using the methods described in Example 2, but substituting the estersdescribed in Examples 1, 9, 10, 11 and 12, the following acids wereprepared:

N- 1-(2(S),3-Diaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine tristrifluoroacetate

FAB MS 516 (M+1).

N-1-(2-(S)Amino-3-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninebis trifluoroacetate

Anal. Calcd for C₃₄ H₄₃ N₅ O₆ S.2.8 CF₃ CO₂ H: C, 49.08; H, 4.76; N,7.23; Found: C, 48.97; H, 4.83; N, 7.26.

N-1-(3-Amino-2(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninebis trifluoroacetate

FAB MS 650 (M+1).

N-1-(L-Glutaminyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)-glycyl-methioninebis hydrochloride

Anal. Calcd for C₂₈ H₃₉ N₅ O₅ S.3.5 HCl: C, 49.07; H, 6.25; N, 10.22;Found: C, 49.11; H, 6.24; N, 10.08.

N-1-(L-Histidinyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)-glycyl-methioninetris trifluoroacetate

FAB MS 567 (M+1).

N-1-(D-Histidinyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)-glycyl-methioninetris trifluoroacetate

FAB MS 567 (M+1).

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninesulfone trifluoroacetate

Anal. Calcd for C₂₈ H₃₅ N₅ O₆ S.3 CF₃ CO₂ H.1.65 H₂ O: C, 43.38; H,4.42; N, 7.44; Found: C, 43.35; H, 4.19; N, 7.78.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₅ H₃₄ N₄ O₄ S.2.9 CF₃ CO₂ H: C, 45.26; H, 4.55; N,6.86; Found: C, 45.05; H, 4.66; N, 7.23.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine sulfonetrifluoroacetate

Anal. Calcd for C₂₅ H₃₄ N₄ O₆ S.2.5 CF₃ CO₂ H.0.6 H₂ O: C, 44.24; H,4.67; N, 6.88; Found: C, 44.25; H, 4.58; N, 6.90.

N- 1-(β-Alanyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₆ H₃₆ N₄ O₄ S.3.25 CF₃ CO₂ H: C, 44.80; H, 4.54; N,6.43; Found: C, 44.74; H, 4.66; N, 6.63.

N- 1-(Sarcosyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninehydrochloride

Anal. Calcd for C₂₆ H₃₆ N₄ O₄ S.2.95 HCl.0.75 H₂ O: C, 50.23; H, 6.56;N, 9.01; Found: C, 50.23; H, 6.32; N, 8.87.

N- 1-(N,N-Dimethylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₇ H₃₈ N₄ O₄ S.3.8 CF₃ CO₂ H: C, 43.84; H, 4.44; N,5.91; Found: C, 43.73; H, 4.66; N, 6.30.

N-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₃₆ H₄₀ N₆ O₄ S.3.10 CF₃ CO₂ H.0.25 H₂ O: C, 50.15; H,4.35; N, 8.31; Found: C, 50.15; H, 4.38; N, 8.09.

N-1-(2-Acetylamino-3(S)-benzyloxycarbonylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

FAB MS 692 (M+1)

N-1-(2-Acetylamino-3(S)-aminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₈ H₃₉ N₅ O₅ S.2.9 CF₃ CO₂ H.1.85 H₂ O: C, 42.33; H,4.44; N, 6.91; Found: C, 42.33; H, 4.43; N, 7.17.

N-1-(2-Amino-3(S)-acetylaminopropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

FAB MS 558 (M+1)

N-1-(Seryl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₆ H₃₆ N₄ O₅ S.3.15 CF₃ CO₂ H: C, 44.30; H, 4.51; N,6.40; Found: C, 43.98; H, 4.44; N, 6.77.

N- 1-(D-Alanyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninehydrochloride

Anal. Calcd for C₂₆ H₃₆ N₄ O₄ S.2.85 HCl.0.4 EtOAc: C, 51.81; H, 6.62;N, 8.76; Found: C, 51.88H, 6.51; N, 8.76.

N-1-(1H-Imidazol-4-carbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₇ H₃₃ N₅ O₄ S.3.5 CF₃ CO₂ H: C, 44.26; H, 3.99; N,7.59; Found: C, 43.93; H, 4.25; N, 7.98.

N- 1-(Isoasparagyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₇ H₃₇ N₅ O₅ S.2.5 CF₃ CO₂ H.0.4 H₂ O: C, 45.98; H,4.86; N, 8.38; Found: C, 45.97; H, 4.88; N, 8.36.

N- 1-(1H-Imidazol-4-propionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₉ H₃₇ N₅ O₄ S.2.8 CF₃ CO₃ H: C, 47.71; H, 4.61; N,8.04; Found: C, 47.60; H, 4.61; N, 8.04.

N- 1-(3-Pyridylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₃₀ H₃₆ N₄ O₄ S.3.45 CF₃ CO₂ H.1.3 H₂ O: C, 45.90; H,4.39; N, 5.80; Found: C, 45.86; H, 4.11; N, 6.20.

N- 1-(2-Pyridylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₃₀ H₃₆ N₄ O₄ S.2.85 CF₃ CO₂ H: C, 49.08; H, 4.48; N,6.41; Found: C, 49.02; H, 4.66; N, 6.75.

N- 1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₃₀ H₃₇ N₅ O₄ S.2.95 CF₃ CO₂ H: C, 47.91; H, 4.47; N,7.78; Found: C, 47.67; H, 4.58; N, 8.15.

N-1-(1H-Imidazol-4-ylmethyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

FAB MS 510 (M+1).

N-1-(2-Aminoethyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₅ H₃₆ N₄ O₃ S.3 CF₃ CO₂ H.1.45 H₂ O: C, 44.28; H,5.02; N, 6.66; Found: C, 44.26; H, 4.78; N, 6.99.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl(β-acetylamino)alaninetrifluoroacetate

Anal. Calcd for C₂₈ H₃₄ N₆ O₅.2.6 CF₃ CO₂ H.0.7 H₂ O: C, 47.26; H, 4.54;N, 9.96; Found: C, 47.29; H, 4.47; N, 9.96.

FAB MS 535 (M+1).

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl(β-acetylamino)alaninetrifluoroacetate

Anal. Calcd for C₂₅ H₃₃ N₅ O₅.3.0 CF₃ CO₂ H.1.0 H₂ O: C, 44.13; H, 4.54;N, 8.30; Found: C, 44.13; H, 4.49; N, 8.59.

FAB MS 484 (M+1).

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(2-thienyl)alaninetrifluoroacetate

Anal. Calcd for C₂₇ H₃₂ N₄ O₄ S.2.4 CF₃ CO₂ H.0.5 H₂ O: C, 48.27; H,4.51; N, 7.08; Found: C, 48.26; H, 4.51; N, 7.09.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(N,N-dimethyl)glutaminetrifluoroacetate

Anal. Calcd for C₃₀ H₃₈ N₆ O₅.3.1 CF₃ CO₂ H.0.9 H₂ O: C, 46.63; H, 4.64;N, 9.01; Found: C, 46.59; H, 4.59; N, 9.22.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(trifluoromethyl)alaninesodium salt N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(2(S)-amino-4-acetylamino)butyricacid sodium salt N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(benzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₄ H₃₃ N₅ O₄ S.2.2 CF₃ CO₂ H.2.0 H₂ O: C, 44.04; H,5.10; N, 9.04; Found: C, 44.03; H, 5.10; N, 8.95.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(benzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₁ H₃₂ N4O₄ S.3.5 CF₃ CO₂ H.1.0 H₂ O: C, 39.40; H,4.43; N, 6.56; Found: C, 39.37; H, 4.41; N, 6.82.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(4-methoxybenzyl)glycyl-methionine

FAB MS 518 (M+1)

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₃₀ H₃₉ N₅ O₄ S.3.45 CF₃ CO₂ H: C, 46.21; H, 4.46; N,7.30; Found: C, 46.24; H, 4.61; N, 7.53.

N- 1-(Glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₇ H₃₈ N₄ O₄ S.3.15 CF₃ CO₂ H.1.55 H₂ O: C, 44.35; H,4.95; N, 6.21; Found: C, 44.36; H, 4.69; N, 6.61.

N-1-(Glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(benzyl)glycyl-methioninebis hydrochloride

Anal. Calcd for C₂₃ H₃₆ N₄ O₄ S.2 HCl.1.0 H₂ O: C, 49.72; H, 7.26; N,10.09; Found: C, 49.92; H, 7.07; N, 9.59.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(benzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₆ H₃₇ N₅ O₄ S.3.2 CF₃ CO₂ H: C, 44.19; H, 4.60; N,7.95; Found: C, 44.13; H, 4.98; N, 8.35.

N-1-(L-Prolyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

FAB MS 527 (M+1)

N-1-(1-Morpholinoacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

FAB MS 557 (M+1)

N-1-(4-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninebis trifluoroacetate

Anal. Calcd for C₂₉ H₄₀ N₄ O₄ S.2.3 CF₃ CO₂ H.0.9 H₂ O: C, 49.26; H,5.42; N, 6.84; Found: C, 49.29; H, 5.39; N, 6.95.

N-1-(3-Piperidinecarbonyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₉ H₄₀ N₄ O₄ S.2.6 CF₃ CO₂ H.1.7 H₂ O: C, 47.34; H,5.34; N, 6.46; Found: C, 47.37; H, 5.33; N, 6.72.

N-1-(2-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₃₀ H₃₇ N₅ O₄ S.2.5 CF₃ CO₂ H.0.8 H₂ O: C, 48.70; H,4.80; N, 8.11; Found: C, 48.72; H, 4.73; N, 8.35.

N-1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₃₀ H₃₇ N₅ O₄ S.2.95 CF₃ CO₂ H: C, 47.91; H, 4.47; N,7.78; Found: C, 47.67; H, 4.58; N, 8.15.

N-1-(4-Pyridyl(N-methyl)glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₃₁ H₃₉ N₅ O₄ S.2.95 CF₃ CO₂ H.0.7 H₂ O: C, 47.83; H,4.72; N, 7.56; Found: C, 47.63; H, 4.80; N, 7.95.

N- 1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninetrifluoroacetate

Anal. Calcd for C₂₉ H₃₆ N₆ O₅.4.1 CF₃ CO₂ H.2.1 H₂ O: C, 42.87; H, 4.31;N, 8.15; Found: C, 42.87; H, 4.25; N, 8.26.

N- 1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninetrifluoroacetate

Anal. Calcd for C₂₉ H₃₆ N₆ O₅.3.1 CF₃ CO₂ H.0.9 H₂ O: C, 46.74; H, 4.43;N, 9.03; Found: C, 46.71; H, 4.41; N, 9.27.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(N-methyl)glutaminetrifluoroacetate

Anal. Calcd for C₂₉₀ H₃₆ N₆ O₅.1.7 CF₃ CO₂ H.0.9 H₂ O: C, 44.31; H,4.29; N, 8.52; Found: C, 44.33; H, 4.28; N, 8.40.

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-methylcarbonylamino)alaninetrifluoroacetate

Anal. Calcd for C₂₈ H₃₅ N₇ O₅.1.2 CF₃ CO₂ H.0.6 H₂ O: C, 44.65; H, 4.29;N, 10.60; Found: C, 44.66; H, 4.40; N, 9.63.

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-methylsulfonylamino)alaninetrifluoroacetate

Anal. Calcd for C₂₇ H₃₄ N₆ O₆ S.2.8 CF₃ CO₂ H.0.9 H₂ O: C, 43.21; H,4.29; N, 9.27; Found: C, 43.21; H, 4.30; N, 9.40.

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-propionylamino)alaninetrifluoroacetate

Anal. Calcd for C₂₉ H₃₆ N₆ O₅.3.1 CF₃ CO₂ H.2.0 H₂ O: C, 45.07; H, 4.63;N, 8.96; Found: C, 45.06; H, 4.56; N, 9.08.

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-pyrrolidinon-1-ylamino)alaninetrifluoroacetate

Anal. Calcd for C₃₀ H₃₆ N₆ O₅.3.4 CF₃ CO₂ H.2.7 H₂ O: C, 44.34; H, 4.53;N, 8.43; Found: C, 44.32; H, 4.47; N, 8.74.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(3-methoxybenzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₅ H₃₅ N₅ O₅ S.2.75 CF₃ CO₂ H: C, 44.07; H, 4.58; N,8.43; Found: C, 43.98; H, 4.82; N, 8.62.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₅ H₃₅ N₅ O₅ S.2.95 CF₃ CO₂ H.0.95 H₂ O: C, 42.60; H,4.61; N, 8.04; Found: C, 42.56; H, 4.48; N, 8.00.

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(3-methoxybenzyl)glycyl-methioninehydrochloride

Anal. Calcd for C₂₂ H₃₄ N₄ O₅ S.3.65 HCl: C, 44.06; H, 6.33; N, 9.34;Found: C, 43.99; H, 6.46; N, 9.36.

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₂ H₃₄ N₄ O₅ S.3.1 CF₃ CO₂ H.0.6 H₂ O: C, 40.77; H,4.65; N, 6.74; Found: C, 40.74; H, 4.67; N, 7.00.

N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₆ H₃₇ N₅ O₅ S.2.9 CF₃ CO₂ H.1.1 H₂ O: C, 43.30; H,4.81; N, 7.94; Found: C, 43.28; H, 4.75; N, 7.98.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(3-cyanobenzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₅ H₃₂ N₆ O₄ S.4.3 CF₃ CO₂ H.0.8 H₂ O: C, 39.67; H,3.76; N, 8.26; Found: C, 39.65; H, 3.75; N, 8.62.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(4-cyanobenzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₅ H₃₂ N₆ O₄ S.2.5 CF₃ CO₂ H.1.4 H₂ O: C, 43.79; H,4.57; N, 10.21; Found: C, 43.85; H, 4.57; N, 10.13.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₅ H₃₂ N₆ O₄ S.3.5 CF₃ CO₂ H.1.4 H₂ O: C, 41.02; H,4.12; N, 8.97; Found: C, 41.03; H, 4.05; N, 9.01.

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₂ H₃₁ N₅ O₄ S.3.0 CF₃ CO₂ H .0.6 H₂ O: C, 41.29; H,4.36; N, 8.60; Found: C, 41.29; H, 4.33; N, 8.67.

N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₆ H₃₄ N₆ O₄ S.4.1 CF₃ CO₂ H.1.0 H₂ O: C, 40.23; H,4.06; N, 8.23; Found: C, 40.20; H, 4.01; N, 8.50.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methylbenzyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₅ H₃₅ N₅ O₄ S.3.2 CF₃ CO₂ H: C, 43.52; H, 4.44; N,8.08; Found: C, 43.54; H, 4.62; N, 8.20.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-trifluoromethylbenzyl)glycyl-methionineN-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylsulfonyl)glycyl-methioninetrifluoroacetate

Anal. Calcd for C₂₇ H₃₃ N₅ O₆ S₂.1.8 CF₃ CO₂ H: C, 46.35; H, 4.42; N,8.83; Found: C, 46.39; H, 4.48; N, 9.20.

Example 3 Preparation of N-1-(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-(Pyrrolidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)-glycyl-methioninemethyl ester hydrochloride(0.200 g, 0.387 mmol), L-pyroglutamic acid(0.060 g, 0.465 mmol) and diisopropylethylamine (0.300 mL, 2.32 mmol)were dissolved in dry DMF (2 mL). BOP-chloride (0.355 mg, 1.39 mmol) wasadded and the mixture stirred under Ar for 18 h. The solvent was removedin vacuo and the residue partitioned between saturated NaHCO₃ soln andEtOAc. The layers were separated and the organics were washed with H₂ O,brine, dried over MgSO₄, filtered and the solvent removed in vacuo togive an oil which was chromatographed on silica gel (3:97 MeOH:CH₂ Cl₂)to give the title compound. ¹ H NMR (CD₃ OD) δ8.33 (d, 1H, J=8 Hz), 7.91(d, 1H, J=7 Hz), 7.85 (d, 1H, J=8 Hz), 7.43-7.64 (m, 4H), 4.36-4.54 (m,3H), 3.98 (d, 1H, J=13 Hz), 3.69 (s, 3H), 3.49-3.58 (m, 1H), 3.21-3.49(m, 5H), 2.92 (dd,1H, J=4, 12 Hz), 2.50-2.59 (m, 1H), 2.25-2.50 (m, 3H),2.08-2.25 (m, 1H), 1.79-2.08 (m, 5H), 1.95 (s, 3H), 1.70-1.79 (m, 1H),1.46-1.57 (m, 1H). FAB MS 555 (M+1).

Anal. Calcd for C₂₉ H₃₈ N₄ O₅ S.0.95 H₂ O: C, 60.91; H, 7.03; N, 9.80.Found: C, 60.89; H, 6.67; N, 9.59.

Example 4 Preparation of N-1-(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(L-Pyroglutamyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester from Example 3 was hydrolyzed to give the title compound. ¹H NMR (CD₃ OD) δ8.34-8.48 (m, 1H), 8.04 (d, 1H, J=8 Hz ), 7.99 (d, 1H,J=8 Hz), 7.70 (t, 1H, J=8 Hz), 7.52-7.66 (m, 3H), 4.33-4.77 (m, 3H),3.35-3.84 (m, 4H), 2.26-2.54 (m, 3H), 2.14-2.26 (m, 1H), 1.78-2.14 (m,4H), 2.03 (s, 3H), 1.64-1.78 (m, 1H).

Anal. Calcd for C₂₈ H₃₆ N₄ O₅ S.1.75 CF₃ CO₂ H: C, 51.11; H, 5.14; N,7.57. Found: C, 50.98; H, 5.42; N, 7.77.

Example 5 Preparation of 2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxyl!-3-phenylpropionyl-methioninemethyl ester

Step A: Preparation of N-Chloroacetyl-2(S)-hydroxymethypyrrolidine

To a solution of 2(S)-hydroxymethylpyrrolidine (25.32 g, 250.3 mmol) inCH₂ Cl₂ (720 mL) under argon was added Et₃ N (38.0 mL, 273 mmol). Aftercooling this mixture to -20° C., chloroacetyl chloride (20.0 mL, 251mmol) was added dropwise over 0.75 h maintaining the reactiontemperature at -20 ±3° C. The reaction was stirred at ambienttemperature for 18 h and evaporated in vacuo. An impurity whichprecipitated during concentration was removed by filtration. The crudeproduct was purified by chromatography (silica gel, 1:39 to 1:19MeOH/CH₂ Cl₂) to give the title compound as a yellow oil. ¹ H NMR(CDCl₃, 400 MHz): δ4.37 (dd, J=8, 3 Hz, 1H), 4.22 (qd, J=7, 3 Hz, 1H),4.08 (s, 2H), 3.71 (td, J=8, 3 Hz, 1H), 3.68-3.50 (m, 3H), 2.14-1.86 (m,3H), 1.72-1.62 (m, 1H).

Step B: Preparation of 6(S)-₂ -Oxo-1-aza-4-oxabicyclo- 4.3.0!-nonane

To a solution of N-chloroacetyl-2(S)-hydroxymethypyrrolidine (12.8 g,71.9 mmol) in THF (240 mL, distilled from Na/benzophenone) under argonat 0° C. was added NaH (3.16 g of a 60% dispersion in mineral oil, 78.9mmol) slowly in several portions. After complete addition , the reactionwas stirred at ambient temperature for 18 h. The reaction was quenchedby adding HOAc (400 μL), diluted with toluene, and evaporated in vacuoto give a thick gray liquid. Water was cautiously added dropwise untilno further gas evolution was observed. This mixture was diluted withMeOH and CH₂ Cl₂ and dried (Na₂ SO₄). Since filtration was unsuccessful,silica gel (60 g) was added and the mixture was evaporated in vacuo. Thecrude product was purified by chromatography (silica gel, 7:13 to 1:1EtOAc/CH₂ Cl₂) to give the title compound as a white solid. ¹ H NMR(CDCl₃, 400 MHz): δ4.25 (d, J=17 Hz, 1H), 4.19 (dd, J=12, 4 Hz, 1H),4.02 (d, J=17 Hz, 1H), 3.76-3.64 (m, 2H), 3.50 (td, J=10, 2.5 Hz, 1H),3.24 (dd, J=12, 10 Hz, 1H), 2.09-1.99 (m, 2H), 1.92-1.78 (m, 1H), 1.39(qd, J=12, 8 Hz, 1H).

Step C: Preparation of3(R),6(S)-2-Oxo-3-(phenylmethyl)-1-aza-4-oxabicyclo- 4.3.0!-nonane and3(S),6(S)-₂ -Oxo-3-(phenylmethyl)-1-aza-4-oxabicyclo- 4.3.0!-nonane(93:7 respectively)

A solution of 6(S)-₂ -oxo-1-aza-4-oxabicyclo- 4.3.0!-nonane (6.013 g,42.60 mmol) in THF (170 mL, distilled from Na/benzophenone) was cooledto -78° C. under argon and transferred via cannula to a second flaskcontaining 1.0M lithium bis(trimethylsilyl)amide in THF (52 mL, 52 mmol)also at -78° C. under argon. After stirring for 0.5 h at -78° C., benzylbromide (7.20 mL, 60.5 mmol) was added dropwise over 5 min. The reactionwas stirred for 1 h at -78° C. followed by 1 h at -50 ° C. The reactionwas quenched by adding saturated aq NH₄ Cl (60 mL) and warming toambient temperature. The reaction was diluted with H₂ O (60 mL) andsaturated aq NaCl (180 mL), and the layers were separated. The aqueouslayer was extracted twice with EtOAc (300, 200 mL). The organic extractswere washed in succession with saturated aq NaCl (150 mL), combined,dried (Na₂ SO₄), and evaporated in vacuo. The crude product was purifiedby chromatography (silica gel, 1:4 EtOAc/CH₂ Cl₂) to give the titlecompound as a yellow oil. ¹ H NMR (CDCl₃, 400 MHz) δ7.31-7.19 (m, 5H),4.44 (dd, J=10, 4 Hz, 0.07H), 4.27 (dd, J=8, 4 Hz, 0.93H), 4.12 (dd,J=12, 4 Hz, 0.93H), 3.94 (dd, J=12, 5 Hz, 0.07H), 3.72-3.62 (m, 1H),3.54-3.18 (m, 4H), 3.01 (dd, J=15, 8 Hz, 0.93H), 3.00 (dd, J=14, 8 Hz,0.07H), 2.04-1.91 (m, 2H), 1.83-1.69 (m, 1H), 1.33 (qd, J=11, 8 Hz, 1H).

Step D: Preparation of3(R),6(S)-2-Oxo-3-(phenylmethyl)-1-aza-4-oxabicyclo- 4.3.0!-nonane and3(S),6(S)-2-Oxo-3-(phenylmethyl)-1-aza-4-oxabicyclo- 4.3.0!-nonane (2:1respectively)

A solution of 3(R,S),6(S)-2-oxo-3-(phenylmethyl)-1-aza-4-oxabicyclo-4.3.0!-nonane (8.818 g, 38.12 mmol) in THF (170 mL, distilled fromNa/benzophenone) was cooled to -78° C. under argon and transferred viacannula to a second flask containing 1.0M lithiumbis(trimethylsilyl)amide in tetrahydrofuran (57 mL, 57 mmol) also at-78° C. under argon. After stirring for 10 min at -78° C., the reactionwas placed in an ice bath for 0.5 h. The reaction was again cooled to-78° C. for 10 min, quenched by adding HOAc (3.30 mL), and allowed towarm to ambient temperature. The reaction was diluted with H₂ O (50 mL)and saturated aq NaCl (100 mL) and extracted twice with EtOAc (300, 200mL). The organic extracts were combined, washed with saturated aq NaCl(200 mL), dried (Na₂ SO₄), and evaporated in vacuo to give the titlecompound as a golden orange oil. ¹ H NMR (CDCl₃, 400 MHz) δ7.34-7.15 (m,5H), 4.43 (dd, J=10, 3 Hz, 0.33H), 4.27 (dd, J=8, 3 Hz, 0.67H), 4.11(dd, J=11, 4 Hz, 0.67H), 3.94 (dd, J=11, 4 Hz, 0.33H), 3.74-3.17 (m,5H), 3.07 (dd, J=14, 10 Hz, 0.33H), 3.01 (dd, J=14, 8 Hz, 0.67H),2.06-1.91 (m, 2H), 1.89-1.71 (m, 1H), 1.39-1.24 (m, 1H).

Step E: Preparation of 2(R)-Pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionic acid hydrochloride and2(S)- Pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionic acid hydrochloride(2:1 mixture)

3(R and S),6(S)-2-Oxo-3-(phenylmethyl)-1-aza-4-oxabicyclo- 4.3.0!-nonane(8.569 g, 37.05 mmol) was dissolved in 6N aq HCl (400 mL) and stirred atreflux under argon for 24 h. The reaction was cooled to ambienttemperature, evaporated in vacuo, diluted with toluene, evaporated invacuo, diluted with toluene, and evaporated in vacuo to give the titlecompound as an orange oil. ¹ H NMR (CD₃ OD, 400 MHz) δ7.35-7.10 (m, 5H),4.33-4.26 (m, 1H), 3.84-3.53 (m, 3H), 3.30-3.09 (m, 3H), 3.05-2.96 (m,1H), 2.17-1.88 (m, 3H), 1.80-1.65 (m, 1H).

Step F: Preparation of 2(R)-1-(t-Butoxycarbonyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionic acidand 2(S)-1-(t-Butoxycarbonyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionic acid(2:1 mixture)

2(R,S)-(Pyrrolidin-2(S)-ylmethyloxy)-3-phenylpropionic acidhydrochloride (9.48 g, 33.2 mmol) was dissolved in H₂ O (70 mL) andneutralized with 1.0N aq NaOH (approx. 40 mL). To this mixture was addeda solution of Na₂ CO₃ (7.304 g, 68.91 mmol) in H₂ O (40 mL). Theresulting mixture (pH=11.5) was cooled to 0° C. under argon;di-tert-butyl dicarbonate (8.2 mL, 36 mmol) was added followed by THF(50 mL). The reaction was stirred at ambient temperature for 18 h,cooled to 0° C., acidified to pH=3 with 10% aq citric acid, andextracted with EtOAc (2×250 mL). The organic extracts were washed insuccession with saturated aq NaCl (250 mL), combined, dried (Na₂ SO₄),and evaporated in vacuo to give the title compound as an orangish-brownoil. ¹ H NMR (CD₃ OD, 400 MHz) δ7.29-7.17 (m, 5H), 4.05-3.99 (m, 1H),3.82-3.77 (m, 1H), 3.69-3.59 (m, 1H), 3.54-3.16 (m, 2H), 3.13-2.97 (m,2H), 2.94-2.85 (m, 1H), 1.88-1.62 (m, 4H), 1.42 (s, 9H).

Step G: Preparation of 2(S)-1-(t-Butoxycarbonyl)pyrrolidin-2(S)-ylmethyloxyl!-3-phenylpropionyl-methioninemethyl ester

To a solution of 2(R and S)-1-(t-butoxycarbonyl)-pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionic acid(263.6 mg, 0.754 mmol) in DMF (8.0 mL) were added3-hydroxy-1,2,3-benzotriazin-4(3H)-one (HOOBT, 137 mg, 0.840 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 164mg, 0.855 mmol), L-methionine methyl ester hydrochloride (176 mg, 0.881mmol), and Et₃ N (0.35 mL, 2.5 mmol). The reaction was stirred underargon at ambient temperature for 18 h, diluted with EtOAc (70 mL), andwashed with 10% aq citric acid (70 mL), saturated aq NaHCO₃ (40, 20 mL),and saturated aq NaCl (40 mL). The organic layer was dried (Na₂ SO₄) andevaporated in vacuo. The diastereomeric crude products were purified andseparated by chromatography (silica gel, 1:19 to 1:2 EtOAc/CH₂ Cl₂) togive the title compound. ¹ H NMR (CD₃ OD, 400 MHz) δ7.35-7.17 (m, 5H),4.63-4.55 (m, 1H), 4.08-3.90 (m, 2H), 3.72 (s, 3H), 3.55-3.46 (m, 2H),3.34-3.22 (m, 1H), 3.09 (dd, J=14, 4 Hz, 1H), 2.91 (dd, J=14, 7 Hz, 1H),2.38-2.20 (m, 2H), 2.10-2.00 (m, 1H), 2.04 (br s, 3H), 1.97-1.86 (m,6H), 1.44 (s, 9H).

Step H: Preparation of 2(S)-1-Pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methionine methyl esterhydrochloride

2(S)-N-(tert-Butoxycarbonyl)-2(S)-(pyrrolidinyl)-methyloxy!-3-phenylpropionyl-methioninemethyl ester (2.138 g, 4.322 mmol) was dissolved in EtOAc (80 mL). Themixture was cooled to 0° C. and HCl gas was bubbled in until saturated.The mixture was stirred at ambient temperature for 1.25 h and evaporatedin vacuo to give the title compound as a yellow foam which was usedwithout further purification. ¹ H NMR (CD₃ OD, 400 MHz) δ7.35-7.20 (m,5H), 4.67 (dd, J=10, 5 Hz, 1H), 4.21 (dd, J=8, 5 Hz, 1H), 3.81-3.75 (m,2H), 3.75 (s, 3H), 3.58 (q, J=6 Hz, 1H), 3.30-3.11 (m, 3H), 2.99 (dd,J=14, 8 Hz, 1H), 2.53-2.36 (m, 2H), 2.19-2.10 (m, 1H), 2.08 (s, 3H),2.07-1.88 (m, 4H), 1.79-1.68 (m, 1H).

Step I: Preparation of 2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester

2(S)-(Pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methionine methylester hydrochloride (1.892 g, 4.390 mmol) was dissolved in CH₂ Cl₂ (33mL). To this solution were added (S)-(-)-2-pyrrolidone-5-carboxylic acid(853.1 mg, 6.607 mmol) and Et₃ N (3.0 mL, 21.5 mmol). This mixture wascooled to 0° C. under argon and treated withbis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP--Cl, 1.70 g, 6.68mmol). After stirring for 18 h at ambient temperature, the reaction wasdiluted with EtOAc (250 mL) and washed with 10% aq citric acid (200 mL),saturated aq NaHCO₃ (200 mL), and saturated aq NaCl (200 mL). Theorganic layer was dried (Na₂ SO₄) and evaporated in vacuo. The crudeproduct was purified by chromatography (silica gel, 3:97 to 1:19MeOH/CH₂ Cl₂,) and filtered through a Whatman 0.45 μm PTFE membranefilter to give the title compound as a colorless foam. ¹ H NMR (CD₃ OD,400 MHz) δ7.33-7.17 (m, 5H), 4.66-4.57 (m, 1.2H), 4.50 (dd, J=9, 5 Hz,0.8H), 4.28-4.21 (m, 0.8H), 4.16-4.04 (m, 1.2H), 3.76-3.30 (m, 4H), 3.75(s, 0.6H), 3.71 (s, 2.4H), 3.16-3.05 (m, 1H), 3.01-2.91 (m, 1H),2.50-2.18 (m, 5H), 2.16-1.78 (m, 7H), 2.06 (s, 0.6H), 2.03 (s, 2.4H).FAB HRMS exact mass calcd for C₂₅ H₃₆ N₃ O₆ S: 506.232483 (MH⁺); found506.232889.

Anal. Calcd for C₂₅ H₃₅ N₃ O₆ S: C, 59.39; H, 6.98; N, 8.31. Found: C,59.56; H, 6.84; N, 8.30.

Using the procedures outlined in Example 5 the following esters wereprepared:

2(S)-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester trifluoroacetate

¹ H NMR (CD₃ OD, 400 MHz): δ8.81 (br d, J=1.5 Hz, 0.8H), 8.76 (br d,J=1.5 Hz, 0.2H), 7.38 (br s, 0.8H), 7.30-7.13 (m, 5.2H), 4.63 (dd, J=9,5 Hz, 0.2H), 4.57 (dd, J=9, 5 Hz, 0.8H), 4.34-4.24 (m, 0.2H), 4.20-4.11(m, 1H), 4.06 (dd, J=8, 4 Hz, 0.8H), 3.93 (br d, J=5 Hz, 0.4H),3.91-3.86 (m, 1.6H), 3.75-3.48 (m, 4H), 3.73 (s, 0.6H), 3.70 (s, 2.4H),3.15-3.04 (m, 1H), 3.00-2.88 (m, 1H), 2.46-2.20 (m, 2H), 2.15-1.84 (m,6H), 2.05 (s, 0.6H), 2.02 (s, 2.4H). FAB HRMS exact mass Calcd for C₂₅H₃₅ N₄ O₅ S: 503.232817 (MH⁺); found 503.233360.

Anal. Calcd for C₂₅ H₃₄ N₄ O₅ S.1.40 TFA.0.45 H₂ O: C, 49.81; H, 5.46;N, 8.36. Found: C, 49.83; H, 5.47; N, 8.52.

2(S)-1-(-2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methionineisopropyl ester

¹ H NMR (CD₃ OD, 400 MHz) δ7.33-7.17 (m, 5H), 5.08-4.96 (m, 1H),4.60-4.47 (m, 2H), 4.28-4.20 (m, 1H), 4.14-4.06 (m, 1H), 3.73-3.45 (m,3H), 3.41-3.33 (m, 1H), 3.09 (dd, J=14, 5 Hz, 1H), 3.00-2.90 (m, 1H),2.50-2.18 (m, 5H), 2.08-1.80 (m, 7H), 2.04 (s, 3H), 1.29-1.23 (m, 6H).

FAB HRMS exact mass calcd for C₂₇ H₄₀ N₃ O₆ S: 534.263783 (MH⁺); found534.264446.

2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninesulfone methyl ester

FAB HRMS exact mass calcd for C₂₅ H₃₅ N₃ O₈ S: 538.222312 (MH⁺); found538.221847.

2(S)-1-(Pyrid-3-ylcarboxy)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester trifluoroacetate

¹ H NMR (CD₃ OD, 400 MHz) δ8.81-8.71 (m, 2H), 8.23-8.15 (m, 1H),7.78-7.70 (m, 11H), 7.29-7.18 (m, 5H), 4.58 (dd, J=9, 5 Hz, 1H),4.48-4.40 (m, 1H), 4.14 (dd, J=7, 5 Hz, 1H), 3.89 (dd, J=9, 5 Hz, 1H),3.71 (s, 3H), 3.71-3.64 (m, 1H), 3.62-3.52 (m, 1H), 3.46-3.37 (m, 1H),3.13 (dd, J=14, 5 Hz, 1H), 2.99 (dd, J=14, 7 Hz, 1H), 2.24-2.16 (m, 2H),2.08-1.76 (m, 6H), 1.96 (br s, 3H). FAB HRMS exact mass calcd for C₂₆H₃₄ N₃ O₅ S: 500.221918 (MH⁺); found 500.221414.

2(R)-{2-1-(Naphth-2-yl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine methyl ester hydrochloride

¹ NMR(CD₃ OD, 400 MHz) δ8.97(0.75H, s), 8.91(0.25H, s), 7.93(1H, d,J=8.6 Hz), 7.88(2H, m), 7.80(0.75H, s), 7.72(0.25H, s), 7.56(2H, m),7.49(1H, s), 7.38(1H, m), 7.25-7.05(5H, m), 5.57(2H, m), 4.58(0.25H, dd,J=5 and 9 Hz), 4.51(0.75H, dd, J=5 and 9 Hz), 4.00(1H, dd, J=5 and 8Hz), 4.00-3.83(1H, m), 3.75(1.5H, m), 3.68(0.75H, s), 3.68(0.5H, m),3.62(2.25H, s), 3.52(0.75H, dd, J=6 and 10 Hz), 3.49-3.32(1.25H, m),3.42(0.75H, dd, 6 and 10 Hz), 3.23(1H, m), 3.03(0.75H, dd, J=5.5 and14.5 Hz), 2.97(0.25H, dd, J=5.5 and 14.5 Hz), 2.89(0.75, dd, J=7.5 and14.5 Hz), 2.83(0.25H, dd, J=7.5 and 14.5 Hz), 2.4-1.63(8H, m),2.01(0.75H, s) and 1.98(2.25H, s)ppm. FAB HRMS exact mass calcd for C₃₆H₄₃ N₄ O₅ S 643.295418 (MH+), found 643.29568.

Anal. Calcd for C₃₆ H₄₂ N₄ O₅ S.2.6HCl: C, 58.62; H,6.09; N, 7.60.Found: C, 58.63; H, 5.95; N, 7.92.

2(S)-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyloxyl!-3-phenylpropionyl-methioninemethyl ester trifluoroacetate

FAB MS 531 (M+1)

2(R)-{2-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine methyl ester hydrochloride

Anal. Calcd for C₃₃ H₃₉ N₅ O₅ S.2.45 HCl.1.8 H₂ O: C, 53.60; H, 6.14; N,9.47; Found: C, 53.59; H, 6.15; N, 9.39.

2(R)-{2-1-(4-Nitrobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine methyl ester hydrochloride

Anal. Calcd for C₃₃ H₃₉ N₅ O₇ S.2.15 HCl: C, 53.67; H, 5.70; N, 9.78;Found: C, 53.46; H, 5.81; N, 10.16.

2(R)-{2-1-(4-Methoxybenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine methyl ester hydrochloride

Anal. Calcd for C₃₃ H₄₂ N₄ O₆ S.0.85 HCl.0.55 H₂ O: C, 56.61; H, 6.47;N, 8.00; Found: C, 56.60; H, 6.47; N, 8.37.

2(R)-{2-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-3(S)-ethyl-2(S)-ylmethoxy}-3-phenylpropionyl-methionine methyl ester hydrochloride

FAB MS 646 (M+1)

Example 6 Preparation of 2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninetrifluoroacetate salt

Step A: Preparation of 2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninetrifluoroacetate salt

To a soln of the 2(S)-N-(2(S)-pyroglutamyl)-2(S)-(pyrrolidinyl)methyloxy!-3-phenylpropionyl-methioninemethyl ester (38.7 mg, 0.0765 mmol) in MeOH (2 mL) under argon was added1.0M aq LiOH (90 μL, 0.090 mmol). After stirring at ambient temperaturefor 18 h, the reaction was treated with HOAc (3 drops) and purified bypreparative HPLC using a Nova Prep 5000 Semi Preparative HPLC System anda Waters PrepPak cartridge (47×300 mm, C18, 15 mm, 100 A) eluting with5-95% CH₃ CN/H₂ O (0.1% TFA) at 100 mL/min (Chromatography A conditions)to give the title compound as a white solid after lyophilization. ¹ HNMR (CD₃ OD, 400 MHz) δ7.36-7.21 (m, 5H), 4.67-4.60 (m, 1.25H), 4.54(dd, J=9, 5 Hz, 0.75H), 4.31-4.24 (m, 0.75H), 4.19-4.13 (m, 0.25H),4.13-4.08 (m, 1H), 3.77-3.70 (m, 1H), 3.67-3.37 (m, 3H), 3.20-3.10 (m,1H), 3.04-2.95 (m, 1H), 2.53-1.85 (m, 12H), 2.10 (s, 0.75H), 2.07 (s,2.25). FAB HRMS exact mass Calcd for C₂₄ H₃₄ N₃ O₆ S: 492.216833 (MH⁺);found 492.217898.

Anal. Calcd for C₂₄ H₃₃ N₃ O₆ S.0.70 TFA.0.55 H₂ O: C, 52.48; H, 6.03;N, 7.23. Found: C, 52.45; H, 5.98; N, 7.39.

Using the procedures outlined in Example 6 the following acids wereprepared:

2(S)-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninetrifluoroacetate

¹ H NMR (CD₃ OD, 400 MHz) δ8.86 (s, 0.7H), 8.81 (0.3H), 7.42 (s, 0.7H),7.34-7.17 (m, 5.3H), 4.64 (dd, J=9, 5 Hz, 0.3H), 4.58 (dd, J=9, 5 Hz,0.7H), 4.40-4.29 (m, 0.3H), 4.23-4.15 (m, 1H), 4.08 (dd, J=8, 5 Hz,0.7H), 4.01-3.88 (m, 2H), 3.81-3.40 (m, 4H), 3.21-3.12 (m, 1H),3.03-2.93 (m, 1H), 2.52-1.88 (m, 8H), 2.08 (s, 0.9H), 2.05 (s, 2.1H).FAB HRMS exact mass calcd for C₂₄ H₃₃ N₄ O₅ S: 489.217167 (MH+); found489.217975.

Anal. Calcd for C₂₄ H₃₂ N₄ O₅ S.1.45 TFA.0.50 H₂ O: C, 48.74; H, 5.24;N, 8.45. Found: C, 48.73; H, 5.25; N, 8.54.

2(S)-1-(2(S)-Pyroglutamyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninesulfone

FAB HRMS exact mass calcd for C₂₄ H₃₄ N₃ O₈ S: 524.206662 (MH⁺); found524.207702.

Anal. Calcd for C₂₄ H₃₃ N₃ O₈ S.0.95 TFA.0.65 H₂ O: C, 48.33; H, 5.52;N, 6.53. Found: C, 48.35; H, 5.39; N, 6.73.

2(S)-1-(Pyrid-3-ylcarboxy)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninetrifluoroacetate

¹ H NMR (CD₃ OD, 400 MHz) δ8.81 (br s, 1H), 8.75 (br s, 1H), 8.23 (d,J=9 Hz, 1H), 7.80-7.73 (m, 1H), 7.30-7.18 (m, 5H), 4.55 (dd, J=9, 5 Hz,1H), 4.48-4.40 (m, 1H), 4.13 (dd, J=7, 4 Hz, 1H), 3.89 (dd, J=10, 5 Hz,1H), 3.69 (dd, J=10, 5 Hz, 1H), 3.62-3.52 (m, 1H), 3.45-3.35 (m, 1H),3.14 (dd, J=14, 5 Hz, 1H), 2.99 (dd, J=14, 7 Hz, 1H), 2.28-2.14 (m, 2H),2.12-1.76 (m, 6H), 1.96 (s, 3H). FAB HRMS exact mass calcd for C₂₅ H₃₂N₃ O₅ S: 486.206268 (MH⁺); found 486.205960.

2(R)-{2-1-(Naphth-2-yl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy)!-3-phenylpropionyl-methionine trifluoroacetate

¹ NMR(CD3OD, 400 MHz) δ8.92 (0.75H, s), 8.90 (0.25H, s), 7.92 (2H, d,J=8.4 Hz), 7.87 (2H, m), 7.78 (0.75H, s), 7.71 (0.25H, s), 7.55 (2H, m),7.47 (0.75H, s), 7.36 (1.25H, m), 7.28-7.06 (4H, m), 5.55 (2H, s), 4.53(0.25H, m), 4.48 (0.75H, m), 3.98 (0.75H, br), 3.96 (0.75H, dd, J=4.2Hz), 3.94 (0.25H, dd, J=4 Hz), 3.87 (0.25H, br), 3.79 (1H, d, J=8 Hz),3.73 (1H, d, J=8 Hz), 3.52 (0.75H, dd, J=5.8 Hz), 3.46 (0.25H, dd, J=5.3Hz), 3.43-3.15 (3H, m), 3.04 (0.75H, dd, J=4.5 and 15 Hz), 2.98 (0.25H,dd, J=4.5 and 15 Hz), 2.89 (0.75H, dd, J=7.5 and 14 Hz), 2.83 (0.25H,dd, J=7.5 and 14 Hz), 2.32 (0.5H, m), 2.21 (1.5H, m), 2.01 (0.75H, s),1.99 (2.25H, s), 1.84 (2H, m) and 1.74 (4H, m). FAB HRMS exact masscalcd for C₃₅ H₄₁ N₄ O₅ S 629.279768 (MH+), found 629.27934.

Anal. Calcd for C₃₅ H₄₀ N₄ O₅ S.1.55 TFA.0.90 H2O: C, 55.69; H,5.32; N,6.82. Found: C, 55.67; H, 5.31; N, 6.71.

2(S)-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninelithium salt

FAB MS 517 (M+1), 523 (M+1, -H, +Li)

2(R)-{2-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine trifluoroacetate

Anal. Calcd for C₃₂ H₃₇ N₅ O₅ S.2.25 HCl.0.90 H₂ O: C, 50.02; H, 4.72;N, 7.99; Found: C, 50.01; H, 4.74; N, 7.89.

2(R)-{2-1-(4-Nitrobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine trifluoroacetate

Anal. Calcd for C₃₁ H₃₇ N₅ O₇ S.1.65 HCl.0.45 H₂ O: C, 50.24; H, 4.86;N, 8.54; Found: C, 50.24; H, 4.82; N, 8.93.

2(R)-{2-1-(4-Methoxybenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-2(S)-ylmethoxy}-3-phenylpropionyl-methionine trifluoroacetate

Anal. Calcd for C₃₂ H₄₀ N₄ O₆ S.2.15 HCl.0.85 H₂ O: C, 50.16; H, 5.08;N, 6.45; Found: C, 50.15; H, 5.08; N, 6.55.

2(R)-{2-1-(4-Cyanobenzyl)-1H-imidazol-5-ylacetyl!pyrrolidin-3(S)-ethyl-2(S)-ylmethoxy}-3-phenylpropionyl-methionine lithium salt

FAB MS 632 (M+1), 638 (M+1, -H,+Li)

Example 7 Preparation of 2(S)-1-(Pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester bis trifluoroacetate

Step A: Preparation of 2(S)-1-(Pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester bis trifluoroacetate

2(S)-(Pyrrolidin-2(S)-ylmethyloxy)-3-phenylpropionyl-methionine methylester hydrochloride (76.5 mg, 0.177 mmol) was dissolved in1,2-dichloroethane (1.2 mL). To this mixture were added3-pyridinecarboxaldehyde (17 mL, 0.18 mmol), 4 A sieves (228 mg), andsodium triacetoxyborohydride (183.5 mg, 0.8658 mmol). After stirring atambient temperature under argon for 18 h, the reaction was diluted withEtOAc (15 mL), washed with saturated aq NaHCO₃ (2×15 mL) and saturatedaq NaCl (15 mL), dried (Na₂ SO₄), and evaporated in vacuo. The crudeproduct was purified by preparative HPLC (Chromatography A conditions)to give the title compound after lyophilization. ¹ H NMR (CD₃ OD, 400MHz) δ8.64 (br s, 1H), 8.58 (br s, 1H), 7.98 (d, J=8 Hz, 1H), 7.49 (dd,J=8, 5 Hz, 1H), 7.20-7.06 (m, 5H), 4.66-4.61 (m, 1H), 4.54-4.45 (m, 1H),4.22-4.14 (m, 2H), 3.75-3.68 (m, 1H), 3.66 (s, 3H), 3.62-3.56 (m, 2H),3.15-3.04 (m, 3H), 2.89 (dd, J=14, 9 Hz, 1H), 2.54-2.38 (m, 2H),2.19-2.07 (m, 2H), 1.99 (s, 3H), 1.99-1.79 (m, 4H). FAB HRMS exact masscalcd for C₂₆ H₃₆ N₃ O₄ S: 486.242654 (MH+); found 486.243425.

Example 8 Preparation of 2(S)-1-(Pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninebis trifluoroacetate

Step A: Preparation of 2(S)-1-(Pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninebis trifluoroacetate

To a solution of 2(S)-1-(pyrid-3-ylmethyl)pyrrolidin-2(S)-ylmethyloxy!-3-phenylpropionyl-methioninemethyl ester (20.7 mg, 0.0426 mmol) in MeOH (1.0 mL) at 0° C. underargon was added 1.0M aq LiOH (50 μL, 0.050 mmol). After stirring atambient temperature for 18 h, additional MeOH (1.0 mL) and 1.0M aq LiOH(50 μL, 0.050 mmol) were added. After an additional 24 h of stirring atambient temperature, TFA (2 drops) was added. The crude reaction mixturewas purified directly by preparative HPLC (Chromatography A conditions)to give the title compound after lyophilization. ¹ H NMR (CD₃ OD, 400MHz) δ8.76 (br s, 1H), 8.69 (br s, 1H), 8.20-8.12 (br d, J=7 Hz, 1H),7.67-7.59 (m, 1H), 7.32-7.15 (m, 5H), 4.68 (dd, J=9, 4 Hz, 1H),4.65-4.55 (m, 1H), 4.33-4.26 (m, 2H), 3.85-3.66 (br, 3H), 3.28-3.14 (m,3H), 3.00 (dd, J=14, 9 Hz, 1H), 2.66-2.47 (m, 2H), 2.30-2.18 (m, 2H),2.11 (s, 3H), 2.10-1.89 (m, 4H). FAB HRMS exact mass calcd for C₂₅ H₃₄N₃ O₄ S: 472.227004 (MH⁺); found 472.225954.

Example 9 Preparation ofN-((4-Imidazolyl)methyl-(2S)-pyrrolidinylmethyl)-N-(1-naphthylmethyl)glycyl-methioninemethyl ester tris trifluoroacetate.

Step A: Preparation ofN-((1-Trityl-4-imidazolyl)methyl-(2S)-pyrrolidinylmethyl)-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-((2S)-Pyrrolidinylmethyl)-N-(1-naphthylmethyl)glycyl-methionine methylester hydrochloride (0.2 g, 0.387 mmol) and1-trityl-4-imidzolecarboxaldehyde (0.133 g, 0.387 mmol) were dissolvedin 1,2-dichloroethane (10 ml). Triethylamine (0.108 ml, 0.774 mmol),sodium triacetoxyborohydride (0.164 g, 0.774 mmol), and 3 Å molecularsieves were added and the mixture stirred overnight. EtOAc (60 ml) andsat. NaHCO₃ (30 ml) were added, the mixture filtered and the layersseparated. The organics were washed with water, brine and dried (MgSO₄).The solvent was removed to give the title compound as an oil.

Step B: Preparation ofN-((4-Imidazolyl)methyl-(2S)-pyrrolidinylmethyl)-N-(1-naphthylmethyl)glycyl-methioninemethyl ester tris trifluoroacetate

N-((1-Trityl-4-imidazolyl)methyl-(2S)-pyrrolidinylmethyl)-N-(1-naphthylmethyl)glycyl-methioninemethyl ester (0.3 g, 0.39 mmol) was dissolved in CH₂ Cl₂ (5 mL) andcooled to 0° C. Triethylsilane (0.247 ml, 1.55 mmol) and trifluoroaceticacid (2 ml) were added and the reaction stirred at rt for 1 hr. Thesolvent was removed and the residue partitioned between water (50 ml)and hexane (30 ml). The aqueous layer was lyophilized, prepped, and theproduct lyophilized to give the title compound. FAB MS 524 (M+1).

Using the procedures described in Example 9, but substituting(t-butoxy)carbonylglycinal for 1-trityl-4-imidazolecarboxaldehyde inStep A, N-1-(2-Aminoethyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester trifluoroacetate was prepared.

Anal. Calcd for C₂₆ H₃₈ N₄ O₃ S.3.75 CF₃ CO₂ H: C, 44.01; H, 4.60; N,6.13; Found: C, 43.95; H, 4.65; N, 6.32.

Example 10 Preparation of N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninemethyl ester trifluoroacetate

Step A: Preparation of Methyl2(S)-benzyloxycarbonylamino-3-aminopropionate

A solution of 2(S)-benzyloxycarbonylamino-3-aminopropionoic acid (2.4 g)in methanol at 0° C. was saturated with HCl gas. After stirring for 2 hat 20° C. the solution was evaporated to obtain the title compound. ¹ HNMR (300 MHz, CD₃ OD) δ7.35 (5H, m), 5.13 (2H, s), 4.50 (1H, m), 3.77(3H, s), 3.45 (1H, m), 3.22 (1H, m).

Step B: Preparation of Methyl2(S)-benzyloxycarbonylamino-3-acetylaminopropionate

To a solution of methyl 2(S)-benzyloxycarbonylamino-3-amino propionate(2.5 g) in methylene chloride was added pyridine (20 mL) and aceticanhydride (5 mL). After stirring for 2 h the solution was concentratedin vacuo. The residue was partitioned between ethyl acetate and water.The ethyl acetate layer was extracted w/50 mL each of 2% potassiumhydrogen sulfate, saturated sodium bicarbonate, saturated sodiumchloride, dried over magnesium sulfate and concentrated in vacuo. Uponevaporation pyridine hydrochloride precipitated and was removed byfiltration. The filtrate was evaporated to obtain the title compound. ¹H NMR (300 MHz, CDCl₃) δ7.28 (5H, s), 6.14 (1H, s), 5.97 (1H, d), 5.10(2H, s), 4.41 (1H, m), 3.78 (3H, s), 1.93 (3H, s).

Step C: Preparation of Methyl 2(S)-amino-3-acetylaminopropionate

To a solution of methyl2(S)-benzyloxycarbonylamino-3-acetylaminopropionate (2.2 g ) inethanolic HCl was added 10% Pd/C (0.3 g) under nitrogen atmosphere.Hydrogen was applied to the mixture at 60 psi for 16 h. The mixture wasfiltered and concentrated in vacuo. The residue was triturated withdiethyl ether to obtain the product. NMR (300 MHz, CD₃ OD) δ4.20 (1H,m), 3.88 (3H, s), 3.82 (1H, m), 3.60 (1H, m), 1.99 (3H, s).

Step D: Preparation of N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninemethyl ester trifluoroacetate

Using the procedures outlined in Example 1, but substituting methyl2(S)-amino-3-acetylaminopropionate for methionine methyl ester in StepD, the title compound was prepared.

Anal. Calcd for C₂₉ H₃₆ N₆ O₅.2.9 CF₃ CO₂ H.0.6 H₂ O: C, 46.96; H, 4.54;N, 9.44; Found: C, 46.90; H, 4.51; N, 9.50.

FAB MS 549 (M+1).

Using the methods described in Example 10 the following compounds wereprepared:

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninemethyl ester trifluoroacetate

Anal. Calcd for C₂₆ H₃₅ N₅ O₅.2.8CF₃ CO₂ H.0.5 H₂ O: C, 45.96; H, 4.74;N, 8.48; Found: C, 45.98; H, 4.70; N, 8.92.

FAB MS 498 (M+1).

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(2-thienyl)alaninemethyl ester trifluoroacetate

Anal. Calcd for C₂₈ H₃₄ N₄ O₄ S.2.5 CF₃ CO₂ H.0.2 H₂ O: C, 48.85; H,4.58; N, 6.91; Found: C, 48.84; H, 4.55; N, 6.83.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(N,N-dimethyl)glutaminemethyl ester

Anal. Calcd for C₃₁ H₄₀ N₆ O₅.3.4 CF₃ CO₂ H.0.1 H₂ O: C, 46.99; H, 4.55;N, 8.70; Found: C, 46.95; H, 4.55; N, 8.86.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(trifluoromethyl)alaninemethyl ester

Anal. Calcd for C₂₈ H₃₂ N₅ O₄ F₃ : C, 58.05; H, 5.56; N, 12.00; Found:C, 58.17; H, 5.61; N, 12.31.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(2(S)-amino-4-acetylamino)butyricacid methyl ester

Anal. Calcd for C₃₀ H₃₈ N₆ O₅.2.75 CF₃ CO₂ H.1.0 H₂ O: C, 47.68; H,4.82; N, 9.40; Found: C, 47.69; H, 4.85; N, 9.40.

N- 1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninemethyl ester

Anal. Calcd for C₃₀ H₃₈ N₆ O₅.2.6 CF₃ CO₂ H.3.3 HCl: C, 43.17; H, 4.52;N, 8.58; Found: C, 43.19; H, 4.60; N, 8.58.

N- 1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninemethyl ester

Anal. Calcd for C₃₀ H₃₈ N₆ O₅.4.3 HCl.1.5 H₂ O: C, 49.09; H, 6.02; N,11.08; Found: C, 49.13; H, 6.03; N, 11.03.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-acetylamino)alaninecyclohexyl ester hydrochloride

Anal. Calcd for C₃₁ H₄₃ N₅ O₅.3.0 HCl: C, 55.15; H, 6.87; N, 10.37;Found: C, 55.14; H, 6.89; N, 10.17.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(N-methyl)glutaminemethyl ester

Anal. Calcd for C₃₀ H₃₈ N₆ O₅.2.0 HCl.2.2 CF₃ CO₂ H.1.8 H₂ O: C, 44.97;H, 5.02; N, 9.15; Found: C, 44.96; H, 5.02; N, 9.10.

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-methylcarbonylamino)alaninemethyl ester

Anal. Calcd for C₂₉ H₃₇ N₇ O₅.2.0 HCl.2.4 CF₃ CO₂ H.1.0 H₂ O: C, 43.74;H, 4.71; N, 10.56; Found: C, 43.76; H, 4.72; N, 9.69.

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-methylsulfonylamino)alaninemethyl ester trifluoroacetate

Anal. Calcd for C₂₈ H₃₆ N₆ O₆ S.3.2 CF₃ CO₂ H.0.8 H₂ O: C, 42.86; H,4.27; N, 8.72; Found: C, 42.90; H, 4.23; N, 8.72.

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-propionylamino)alaninemethyl ester trifluoroacetate

Anal. Calcd for C₃₀ H₃₈ N₆ O₅.2.8 CF₃ CO₂ H.1.6 H₂ O: C, 46.95; H, 4.87;N, 9.23; Found: C, 46.92; H, 4.87; N, 9.30.

N- 1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-(β-pyrrolidinon-1-ylamino)alaninemethyl ester

Anal. Calcd for C₃₁ H₃₈ N₆ O₅.1.2 H₂ O: C, 51.00; H, 5.18; N, 10.19;Found: C, 51.02; H, 5.21; N, 10.34.

Example 11

Using the methods described in Example 1, but substituting theappropriate aldehyde for 1-naphthaldehyde in Step B, the followingcompounds were prepared:

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(benzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₅ H₃₅ N₅ O₄ S.2.1 CF₃ CO₂ H.1.9 HCl: C, 43.28; H,4.85; N, 8.64; Found: C, 43.27; H, 4.85; N, 8.65.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(benzyl)glycyl-methioninemethyl ester bis hydrochloride

Anal. Calcd for C₂₂ H₃₄ N₄ O₄ S.2 HCl.1.8 CF₃ CO₂ H: C, 42.19; H, 5.23;N, 7.69; Found: C, 42.13; H, 5.23; N, 7.70.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(4-methoxybenzyl)glycyl-methioninemethyl ester hydrochloride

Anal. Calcd for C₂₆ H₃₇ N₅ O₅ S.2.6 HCl: C, 49.85; H, 6.37; N, 11.18;Found: C, 49.86; H, 6.34; N, 11.06.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(3-methoxybenzyl)glycyl-methioninemethyl ester

FAB MS 532 (M+1)

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₆ H₃₇ N₅ O₅ S.0.5 H₂ O: C, 57.76; H, 7.08; N, 12.95;Found: C, 57.57; H, 6.90; N, 12.73.

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(3-methoxybenzyl)glycyl-methioninemethyl ester hydrochloride

Anal. Calcd for C₂₃ H₃₆ N₄ O₅ S.2.95 HCl: C, 46.97; H, 6.67; N, 9.53;Found: C, 46.75; H, 6.83; N, 9.33.

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₃ H₃₆ N₄ O₅ S.2.0 HCl.1.4 CF₃ CO₂ H.0.9 H₂ O: C,42.49; H, 5.69; N, 7.69; Found: C, 42.49; H, 5.69; N, 7.92.

N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₇ H₃₉ N₅ O₅ S.2.0 HCl.1.9 CF₃ CO₂ H.0.1 H₂ O: C,44.19; H, 5.19; N, 8.37; Found: C, 44.17; H, 5.21; N, 8.21.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(3-cyanobenzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₆ H₃₄ N₆ O₄ S.2.0 HCl.1.4 CF₃ CO₂ H.1.6 H₂ O: C,43.90; H, 5.19; N, 10.66; Found: C, 43.88; H, 5.21; N, 11.02.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₆ H₃₄ N₆ O₄ S.2.0 HCl.1.1 CF₃ CO₂ H.0.4 H₂ O: C,46.26; H, 5.22; N, 11.48; Found: C, 46.29; H, 5.23; N, 11.30.

N-1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₃ H₃₃ N₅ O₄ S.2.0 HCl.1.2 CF₃ CO₂ H.1.2 H₂ O: C,43.15; H, 5.50; N, 9.91; Found: C, 43.14; H, 5.46; N, 9.87.

N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(2-cyanobenzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₇ H₃₆ N₆ O₄ S.2.0 HCl.1.4 CF₃ CO₂ H.0.7 H₂ O: C,45.55; H, 5.23; N, 10.69; Found: C, 45.49; H, 5.21; N, 10.82.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-methylbenzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₆ H₃₇ N₅ O₄ S.0.65 H₂ O: C, 59.21; H, 7.32; N, 13.28;Found: C, 59.21; H, 7.12; N, 13.16.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(2-trifluoromethylbenzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₆ H₃₄ N₅ O₄ F₃ S.0.70 H₂ O: C, 53.63; H, 6.13; N,12.03; Found: C, 53.61; H, 5.93; N, 11.74.

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylsulfonyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₈ H₃₅ N₅ O₆ S.0.95 H₂ O: C, 54.34; H, 6.01; N, 11.32;Found: C, 54.14; H, 5.70; N, 11.40.

Example 12 Preparation of N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

Using the procedures described in the literature for similarintermediates (J. Y. L. Chung, M. W. Holladay et al, J. Org. Chem.,1990, 55, 270-275), the title compound was prepared as described below.

Step A: Diethyl 1-Acetyl-5-hydroxy-3-ethylpyrrolidine-2,2-dicarboxylate

Sodium (4.02 g, 0.175 mol) was dissolved in a stirred solution ofdiethyl acetamidomalonate (235.4 g, 1.19 mol) in abs EtOH (1.4 L) atambient temperature under argon. The reaction mixture was cooled to 0°C., and trans-2-pentenal (100 g, 1.08 mol) was added dropwisemaintaining the reaction temperature at <5° C. After the addition, thereaction was allowed to warm to room temperature, stirred for 4 h, thenquenched with acetic acid (28 mL). The solution was concentrated invacuo, and the residue dissolved in EtOAc (1.5 L), washed with 10%NaHCO₃ solution (2×300 mL), brine, and dried (MgSO₄). The solution wasfiltered and concentrated to 700 mL, then heated to reflux and treatedwith hexane (1 L). On cooling, the title compound precipitated and wascollected to give 287 g. ¹ H NMR (CD₃ OD) δ5.65 (d, 1H, J=5 Hz),4.1-4.25 (m, 4H), 2.7-2.8 (m, 1H), 2.21 (s, 3H), 2.10 (dd, 1H, J=6, 13,Hz),1.86-1.97 (m, 2H), 1.27 (t, 3H, J=7 Hz), 1.23 (t, 3H, J=7 Hz),1.1-1.25 (m, 1H), 0.97 (t, 3H, J=7 Hz).

Step B: Diethyl 1-Acetyl-3-ethylpyrrolidine-2,2-dicarboxylate

To a solution of diethyl1-acetyl-5-hydroxy-3-ethylpyrrolidine-2,2-dicarboxylate (287 g, 0.95mol) and triethylsilane (228 mL, 1.43 mol) in CH₂ Cl₂ (3 L) under argonwas added trifluoroacetic acid (735 mL, 9.53 mol) dropwise with stirringwhile maintaining the internal temperature at 25° C. by means of an icebath. After stirring for 3 h at 23° C., the solution was concentrated invacuo,, the residue diluted with CH₂ Cl₂ (1.5 L), then treated with H₂ O(1 L) and solid Na₂ CO₃ with vigorous stirring until the solution wasbasic. The organic layer was separated, dried (Na₂ SO₄), filtered, thenconcentrated to give the title compound as a yellow oil (373 g) whichwas used without further purification.

Step C: 3-Ethylproline hydrochloride (Cis:Trans Mixture)

Diethyl 1-acetyl-3-ethylpyrrolidine-2,2-dicarboxylate (373 g, 0.95 mol)was suspended in 6N HCl (2 L) and HOAc (500 mL) and heated at reflux for20 h. The reaction mixture was cooled, washed with EtOAc (1L), thenconcentrated in vacuo to give an oil which crystallized upon triturationwith ether to give 170 g of the title compound. ¹ H NMR (D₂ O) δ4.23 (d,1H, J=8 Hz), 3.84 (d, 1H, J=8 Hz), 3.15-3.4 (m, 4H), 2.33-2.44 (m, 1H),2.19-2.4 (m, 1H), 2.02-2.15 (m, 2H), 1.53-1.72 (m, 3H), 1.23-1.43 (m,2H), 1.0-1.15 (m, 1H), 0.75-0.83 (m, 6H).

Step D: Preparation of N- (tert-Butyloxy)carbonyl!-3-ethylproline methylester

3-Ethylproline hydrochloride (Cis:Trans Mixture) (20 g, 0.11 mol) wasdissolved in CH₃ OH (200 mL), and the solution was saturated with HClgas, then stirred at 23° C. for 24 h. Argon was bubbled through thesolution to remove excess HCl. The solution was treated with NaHCO₃ (>84g) to a pH of 8, then di-tert-butyl dicarbonate (25.1 g, 0.115 mol)dissolved in CH₃ OH (20 mL) was added slowly. After stirring for 18 h at23° C., the mixture was filtered, the filtrate concentrated, and theresidue triturated with EtOAc, filtered again, and concentrated to give29.1 g of the title compound as an oil.

Step E: Preparation of N (tert-Butyloxy)carbonyl!-trans-3-ethylprolineand N- -(tert-Butyloxy)carbonyl!-cis-3-ethylproline methyl ester

N- (tert-Butyloxy)carbonyl!-3-ethylproline methyl ester (29.1 g, 0.113mol) was dissolved in CH₃ OH (114 mL) with cooling to 0° C., thentreated with 1N NaOH (114 mL). After stirring for 20 h at 23° C., thesolution was concentrated to remove the CH₃ OH and then extracted withEtOAc (3×). The organic layers were combined, dried (MgSO₄), filtered,and concentrated to give 12.8 g of N-(tert-Butyloxy)carbonyl!-cis-3-ethylproline methyl ester as an oil. Theaqueous layer was acidified with solid citric acid and extracted withEtOAc (2×), the organic layers combined, dried (MgSO₄), filtered, andconcentrated to give 15.5 g of N-(tert-Butyloxy)carbonyl!-trans-3-ethylproline as an oil. ¹ H NMR (CD₃OD) δ3.86 and 3.78 (2 d, 1H, J=6 Hz), 3.33-3.58 (m, 2H), 2.01-2.22 (m,2H), 1.5-1.74 (m, 2H), 1.33-1.5 (m, 1H), 1.45 and 1.42 (2 s, 9H), 0.98(t, 3H, J=8 Hz).

Step F: Preparation of 3(S)-Ethyl-2(S)-proline

N- (tert-Butyloxy)carbonyl!-trans-3-ethylproline (15.5 g, )0.064 mol),S-a-methylbenzylamine (9.03 mL, 0.070 mol), HOBT (10.73 g, 0.70 mol),and N-methylmorpholine (8 mL, 0.076 mol) were dissolved in CH₂ Cl₂ (150mL) with stirring in an ice-H₂ O bath, treated with EDC (13.4 g, 0.070mol) stirred at 23° C. for 48 h. The reaction mixture was partitionedbetween EtOAc and 10% citric acid solution, the organic layer washedwith satd NaHCO₃ solution, brine and dried (MgSO₄), filtered, andconcentrated to give an oil. This oil was dissolved in a minimum amountof ether (10 mL) to crystallize the desired S,S,S diastereomer (4.2 g).A solution of this product in 8N HCl (87 mL) and glacial acetic acid (22mL) was heated at reflux overnight. The solution was concentrated on arotary evaporator, and the residue taken up in H₂ O and extracted withether. The aqueous layer was concentrated to dryness to give 3.8 g of a1:1 mixture of 3(S)-ethyl-2(S)-proline and a-methylbenzylamine.

Step G: Preparation of N-(tert-Butyloxy)carbonyl-3(S)-ethyl-2(S)-prolinol

3(S)-Ethyl-2(S)-proline containing a-methylbenzylamine (2.0 g, 0.0128mol) was dissolved in dioxane (10 mL) and H₂ O (10 mL) with stirring andcooling to 0° C. N,N-diisopropylethylamine (2.2 mL, 0.0128 mol) anddi-tett-butyl-dicarbonate (2.79 g, 0.0128 mol) were added and stirringwas continued at 23° C. for 48 h. The reaction mixture was partitionedbetween EtOAc (60 mL) and H₂ O (30 mL), the organic layer washed with0.5N NaOH (2×40 mL), the aqueous layers combined and washed with EtOAc(30 mL) and this layer back-extracted with 0.5N NaOH (30 mL). Theaqueous layers were combined and carefully acidified at 0° C. with INHCl to pH 2. This mixture was extracted with EtOAc (3×40 mL), theorganics combined, dried (MgSO₄), filtered and concentrated to give N-(tert-Butyloxy)carbonyl-3(S)-ethyl-2(S)-proline as a colorless oil whichwas used without purification.

N- (tert-Butyloxy)carbonyl-3(S)-ethyl-2(S)-proline (1.6 g, 6.58 mmol)was dissolved in dry THF (10 mL) and treated with borane (1M in THF,12.5 mL, 12.5 mmol) with stirring at 0 ° C. for 2 h, then 23° C. for 1h. The solution was cooled to 0° C., treated with H₂ O (20 mL), andextracted with EtOAc (2×30 mL). The organics were washed with brine,satd NaHCO₃, H₂ O, dried (MgSO₄), filtered and concentrated to give aviscous oil. The oil was dissolved in CH₂ Cl₂, filtered through drySiO₂, and the filtrate concentrated to give the title compound as anoil. ¹ H NMR (CDCl₃) δ4.97 (d, 1H, J=7 Hz), 3.71 (t, 1H, J=8 Hz),3.51-3.62 (m, 3H), 3.18-3.26 (m, 1H), 1.9-2.0 (m, 1H), 1.53-1.7 (m, 2H),1.47 (s, 9H), 1.26-1.43 (m, 2H), 0.95 (t, 3H, J=7 Hz).

Step H: Preparation of N- (t-Butyloxy)carbonyl!-3(S)-ethyl-2(S)-prolinal

N- (t-Butyloxy)carbonyl-3(S)-ethyl-2(S)-prolinol (0.638 g, 2.78 mmol)and Et₃ N (1.4 mL, 9.74 mmol) were dissolved in dry CH₂ Cl₂ (10 mL) withstirring and cooling to -10° C. and treated dropwise with a solution ofSO₃.pyr (1.33 g, 8.35 mmol) in dry DMSO (5 mL) keeping the reactionmixture temperature at <0° C. The mixture was stirred at 0° C. for 20min then at 5° C. for 20 min, and at 15° C. for 1 h, then poured intoice-cold 0.5N HCl and the layers separated. The aqueous layer wasextracted with CH₂ Cl₂ (3×20 mL), organics combined, washed with H₂ O,aq satd NaHCO₃ solution, brine, and dried (Na₂ SO₄). Filtration andconcentration to dryness gave the title compound which was used withoutpurification.

Step I: Preparation of N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine methyl ester

Using the procedures described in Example 1, but substituting N-(t-Butyloxy)carbonyl!-3(S)-ethyl-2(S)-prolinal for N-(t-Butyloxy)carbonyl!-2(S)-prolinal in Step A, the title compound wasprepared.

Anal. Calcd for C₃₁ H₄₁ N₅ O₄ S.3.4 CF₃ CO₂ H: C, 46.93; H, 4.63; N,7.24; Found: C, 46.87; H, 4.75; N, 7.56.

Using the procedures described in Example 12, the following compoundswere prepared:

N- 1-(Glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester bis hydrochloride

FAB MS 529 (M+1).

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(benzyl)glycyl-methioninemethyl ester

Anal. Calcd for C₂₇ H₃₉ N₅ O₄ S.3 HCl: C, 50.74; H, 6.62; N, 10.96;Found: C, 50.57; H, 6.65; N, 10.89.

N- 1-(Glycyl)pyrrolidin-3(S)-ethyl-2(S)-ylmethyl!-N-(benzyl)glycyl-methionine methylester bis hydrochloride

Anal. Calcd for C₂₄ H₃₈ N₄ O₄ S.2 HCl: C, 51.42; H, 7.37; N, 10.00;Found: C, 51.23; H, 7.10; N, 9.81.

Example 13 Preparation of N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

Step. A: Preparation of N-(t-Butoxycarbonyl methionine isopropyl ester

N-(t-Butoxycarbonyl methionine (25 g, 0.1 mol), EDC (21.1 g, 0.15 mol),4-dimethylaminopyridine (1.22 g, 0.01 mol), and isopropanol (11.5 mL,0.11 mol) were dissolved in dichloromethane (400 mL) with stirring in anice-H₂ O bath. The mixture was stirred at ambient temperature for 16 hthen concentrated to dryness and partitioned between EtOAc and H₂ O.After standard workup the crude product was chromatographed (SiO₂,hexane: EtOAc, 5:1) to give the title compound.

Step B: Preparation of Methionine isopropyl ester hydrochloride

HCl gas was bubbled into a solution of N-(t-Butoxycarbonyl methionineisopropyl ester (20.5 g, 0.07 mol) in EtOAc (200 mL) with stirring andcooling to -20° C. for 10 min. The flask was stoppered and stirred at-20° C. for 1 h, argon was bubbled into the solution to remove excessHCl, then the solution was concentrated to dryness to give a white solidwhich was used without further purification.

Step C: Preparation of N-1-(1H-imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

Using the methods described in Example 1, but substituting methionineisopropyl ester hydrochloride for methionine methyl ester in Step D, thetitle compound was prepared.

Anal. Calcd for C₃₁ H₄₁ N₅ O₄ S.0.5 H₂ O: C, 63.24; H, 7.19; N, 11.89;Found: C, 63.22; H, 6.91; N, 11.86.

Using the methods outlined in Examples 1 and 13, the following esterswere prepared:

N-1-(1H-Imidazol-4-ylacetyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninesulfone isopropyl ester

Anal. Calcd for C₃₁ H₄₁ N₅ O₆ S.0.35 CH₂ Cl₂ : C, 58.70; H, 6.55; N,10.92; Found: C, 58.59; H, 6.47; N, 11.05.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester bis hydrochloride

Anal. Calcd for C₂₈ H₄₀ N₄ O₄ S.2.5 HCl: C, 54.26; H, 6.91; N, 9.04;Found: C, 54.31; H, 6.98; N, 8.93.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninecyclohexyl ester hydrochloride

Anal. Calcd for C₃₁ H₄₄ N₄ O₄ S.2.8 HCl: C, 55.50; H, 7.03; N, 8.35;Found: C, 55.55; H, 6.95; N, 8.10.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine benzylester hydrochloride

Anal. Calcd for C₃₂ H₄₀ N₄ O₄ S.2.4 HCl 0.1 H₂ O: C, 57.71; H, 6.45; N,8.41; Found: C, 57.75; H, 6.40; N, 8.34.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine ethylester bis hydrochloride

Anal. Calcd for C₂₇ H₃₈ N₄ O₄ S.2 HCl.0.7 H₂ O: C, 54.03; H, 6.95; N,9.33; Found: C, 54.07; H, 6.75; N, 9.19.

N- 1-(Sarcosyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester bis hydrochloride

FAB MS 543 (M+1)

N- 1-(N,N-Dimethylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester hydrochloride

Anal. Calcd for C₃₀ H₄₄ N₄ O₄ S.2.6 HCl: C, 55.30; H, 7.21; N, 8.60;Found: C, 55.28; H, 7.30; N, 8.57.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine(2-pyridylmethyl) ester hydrochloride

Anal. Calcd for C₃₁ H₃₉ N₅ O₄ S.3.35 HCl.0.95 EtOAc: C, 53.34; H, 6.43;N, 8.94; Found: C, 53.40; H, 6.59; N, 8.58.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine(1-glyceryl) ester trifluoroacetate

Anal. Calcd for C₂₈ H₄₀ N₄ O₆ S.2.80 CF₃ CO₂ H.1.5 H₂ O: C, 44.50; H,5.09; N, 6.18; Found: C, 44.51; H, 5.08; N, 6.40.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine4-N-methylpiperidinyl ester tris hydrochloride

Anal. Calcd for C₃₁ H₄₅ N₅ O₄ S.3.85 HCl.0.45 EtOAc: C, 51.58; H, 6.92;N, 9.17; Found: C, 51.58; H, 7.02; N, 9.16.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninetert-butyl ester bis hydrochloride

Anal. Calcd for C₂₉ H₄₂ N₄ O₄ S.2.5 HCl.1.1 H₂ O: C, 53.28; H, 7.20; N,8.57; Found: C, 53.34; H, 7.22; N, 8.57.

N- 1-(Glycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine 3-pentylester bis hydrochloride

Anal. Calcd for C₃₀ H₄₄ N₄ O₄ S.2.0 HCl.1.0 H₂ O: C, 55.63; H, 7.47; N,8.65; Found: C, 55.93; H, 7.38; N, 8.57.

N- 1-(4-Pyridylglycyl)pyrrolidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester hydrochloride

Anal. Calcd for C₃₃ H₄₃ N₅ O₄ S.2.95 HCl: C, 55.56; H, 6.49; N, 9.82;Found: C, 55.63; H, 6.78; N, 9.52.

N-1-(1H-Imidazol-4-ylpropionyl)pyrrolidin-2(S)-ylmethyl!-N-(11-naphthylmethyl)glycyl-methionineisopropyl ester trifluoroacetate

Anal. Calcd for C₃₂ H₄₃ N₅ O₄ S.3.4 CF₃ CO₂ H: C, 47.48; H, 4.77; N,7.14; Found: C, 47.38; H, 4.93; N, 7.41.

Example 14 Preparation of N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

Step A: N-(t-Butoxycarbonyl)piperidine-2(S)-carboxylic acid

2(S)-Piperidinecarboxylic acid (3.0 g, 0.023 mol) was dissolved indioxane (30 mL) water (30 mL) with stirring and cooling in an ice-waterbath, and the solution brought to pH 8 with diisopropylethylamine. Theresulting solution was treated alternately with di-tert-butyldicarbonate (11 mL, 0.048 mol) and diisopropylethylamine (total of 15mL, 0.086 mol ) then stirred at ambient temperature for 16 h. Thereaction mixture was treated with 0.1N NaOH solution (200 mL) andextracted with EtOAc (3×100 mL). The organics were combined, washed withbrine and dried (MgSO₄). Filtration and concentration to dryness gavethe title compound which was used without further purification.

Step B: N-(t-Butoxycarbonyl)piperidinyl-2(S)-methanol

N-(t-Butoxycarbonyl)piperidine-2(S)-carboxylic acid (3.2 g, 0.014 mol)dissolved in THF (20 mL) and cooled in an ice-water bath, was treateddropwise with borane in THF (1M 28 mL, 0.028 mol) maintaining thereaction temperature at <10° C. The solution was stirred at 4° C. for 2h, then at 25° C. for 1 h, then cooled to 0° C. and treated carefullywith water (50 mL). The reaction mixture was extracted with EtOAc (3×50mL), the organics combined, washed with water, aq satd NaHCO₃ solution,brine, and dried (MgSO₄). Filtration and concentration to dryness,followed by chromatography (SiO₂, CH₂ Cl₂ : CH₃ OH, 95:5) gave the titlecompound. ¹ H NMR (CDCl₃) δ4.25-4.35(m, 1H), 3.9-4.0 (m, 1H), 3.79-3.89(m, 1H), 3.56-3.65 (m, 1H) 2.81-2.93 (m, 1H), 2.03 (br s, 1H), 1.53-1.72(m, 5H), 1.46(s, 9H), 1.38-1.52 (m, 3H).

Step C: N-(t-Butoxycarbonyl)piperidine-2(S)-carboxaldehyde

N-(t-Butoxycarbonyl)piperidinyl-2(S)-methanol (2.64 g, 0.01 mol) wasdissolved in anhydrous DMSO (50 mL), treated with Et₃ N (4.8 mL, 0.035mol), stirred for 10 min, then cooled to 15° C. in an ice-water bath,and pyridine.SO₃ complex (5.5 g, 0.035 mol) was added portionwise. After2.5 h, the reaction mixture was treated with ice (50 g), and extractedwith CH₂ Cl₂ (3×75 mL). The organics were combined, washed with 10%citric acid solution, H₂ O, aq satd NaHCO₃ solution, brine, and dried(MgSO₄). Filtration and concentration to dryness gave the title compoundas an oil. ¹ H NMR (CDCl₃) δ9.59 (s, 1H), 4.43-4.67 (m, 1H), 3.83-4.06(m, 1H), 2.81-3.0 (m, 1H), 2.12-2.3 (m, 1H), 1.53-1.72 (m, 3H), 1.47(s,9H), 1.45-1.53 (m, 1H), 1.20-1.34 (m, 1H).

Step D: (1-Naphthylmethyl)glycine methyl ester hydrochloride

1-Naphthylmethanol (5.0 g, 0.0316 mol) was dissolved in dry CH₂ Cl₂ (30mL), diisopropylethylamine (6.6 mL, 0.0379 mol) was added, and thesolution was cooled to 0° C. in an ice-water bath under Ar.Methanesulfonyl chloride (3.2 mL, 0.0316 mol) was added dropwise. Afterstirring cold for 30 min, additional diisopropylethylamine (1.6 mL) andmethanesulfonyl chloride (0.8 mL) were added, and the reaction mixturewas stirred and allowed to warm to 25 ° C. over 2.5 h. This solution wasadded alternately dropwise with diisopropylethylamine (22.5 m, 0.129mol) to a slurry of glycine methyl ester hydrochloride (19.8 g, 0.158mol) and diisopropylethylamine (5 mL, 0.028 mol) in dry DMF (30 mL) at0° C. The reaction mixture was left to warm to ambient temperatureovernight. Solvent was removed, and the residue treated with H₂ O (200mL) and extracted with EtOAc (3×150 mL). The organics were washed withH₂ O, brine, and dried (MgSO₄ and DARCO), filtered and concentrated togive a yellow oil. The oil was dissolved in EtOAc (200 mL), cooled to 0°C., and treated with HCl gas to precipitate the title compound as a tansolid. ¹ H NMR (CDCl₃) δ10.48 (br s, 2H), 8.23 (d, 1H, J=8.6 Hz),7.85-7.9 (m, 3H), 7.65 (td, 1H, J=1, 10 Hz), 7.47-7.58 (m, 2H), 4.84 (s,2H), 3.67 (s, 3H), 3.65 (s, 2H).

Step E: N-(t-Butoxycarbonylpiperidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)glycine methyl ester

N-(t-Butoxycarbonyl)piperidine-2(S)-carboxaldehyde (2.19 g, 0.01 mol),(1-naphthylmethyl)glycine methyl ester hydrochloride (2.66 g, 0.01 mol)and Et₃ N (1.4 mL, 0.01 mol) were dissolved in 1,2-dichloroethane (50mL) with stirring under Ar in an ice-H₂ O bath. Sodiumtriacetoxyborohydride (3.18 g, 0.015 mol) was added in one portion, thebath was removed, and the reaction mixture left to stir overnight atambient temperature. The mixture was partitioned between EtOAc and aqsatd NaHCO₃ solution, the basic layer washed with EtOAc (2×50 mL), theorganics combined, washed with brine, and dried (MgSO₄). Filtration andconcentration to dryness gave the title compound as a pale yellow oilafter chromatography (SiO₂, EtOAc: hexane, 1:6). ¹ H NMR (CDCl₃)δ8.27-8.35 (m, 1H), 7.82 (d, 1H, J=8 Hz), 7.76 (d, 1H, J=8 Hz),7.34-7.53 (m, 4H), 4.36 (d, 1H, J=13 Hz), 4.20 (d, 1H, J=13 Hz),4.2-4.35 (m, 1H), 3.7-3.9 (m, 1H), 3.69 (s, 3H), 3.53 (d, 1H, J=17 Hz),3.37 (d, 1H, J=17 Hz), 2.7-2.9 (m, 2H), 2.35-2.45 (m, 1H), 1.6-1.7 (m,1H), 1.34-1.48 (m, 2H), 1.43 (s, 9H), 1.2-1.3 (m, 2H), 0.9-1.0 (m, 1H).

Step F: N-(t-Butoxycarbonylpiperidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)glycine

N-(t-Butoxycarbonylpiperidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)glycinemethyl ester (3.71 g, 8.7 mmol) was dissolved in MeOH (130 ml) in anice-H₂ O bath, and 1N NaOH (43.5 ml, 43.5 mmol) was added. The mixturewas stirred at ambient temperature for 5 h and concentrated. Theresulting residue was dissolved in H₂ O (50 ml) and neutralized with 1NHCl (43.5 ml). The aqueous layer was washed with EtOAc (3×75 ml). Theorganic layers were combined, dried (MgSO₄), filtered, and concentratedto give the title compound as a white foam.

Step G: Preparation ofN-(t-Butoxycarbonylpiperidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)glycine-methioninemethyl ester

N-(t-Butoxycarbonylpiperidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)glycine(2.00 g, 5.0 mmol), dissolved in CH₂ Cl₂ (50 mL), was treated with HOBT(0.743 g, 5.5 mmol), EDC (1.05 g, 5.5 mmol), and methionine methyl esterhydrochloride (1.20 g, 6.0 mmol). The pH was adjusted to 7.5 with Et₃ N(2.1 mL, 15 mmol) and the mixture was stirred at ambient temperature for18 h. The mixture was diluted with EtOAc (50 mL), washed with 10% citricacid solution, water, and saturated NaHCO₃ solution, brine and dried(MgSO₄). Filtration and concentration gave the title compound. ¹ H NMR(CDCl₃); δ8.21 (d, 1H, J=8 Hz), 7.87 (d, 1H, J=8 Hz), 7.80 (d, 1H, J=8Hz), 7.35-7.6 (m, 5H), 4.33-4.5 (m, 2H), 3.85-4.05 (m, 2H), 3.26 (s,3H), 3.15-3.33 (m, 2H), 2.62-2.96 (m, 1H), 2.53-2.65 (m, 1H), 2.17 (s,3H), 1.78-2.05 (m, 4H), 1.15-1.72 (m, 8H), 1.48 (s. 9H).

Step H: Preparation ofN-(Piperidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)-glycyl-methioninemethyl ester hydrochloride

N-(t-Butoxycarbonylpiperidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)-glycyl-methioninemethyl ester (3.23 g, 5.79 mmol) was dissolved in EtOAc (50 mL) andcooled to 0° C. HCl was bubbled through the mixture for 5 min, then thesolution was stirred at 0° C. for 1.5 h. Argon was bubbled through themixture to remove excess HCl and the mixture was then concentrated togive the title compound. ¹ H NMR (CD₃ OD) δ8.24 (d, 1H, J=8 Hz),7.82-7.91 (m, 2H), 7.42-7.57 (m, 4H), 4.53-4.58 (m, 1H), 4.31 (d, 1H,J=13 Hz), 4.13 (d, 1H, J=13 Hz), 3.68 (s, 3H), 3.45 (ABq, 2H), 3.14-3.21(m, 1H), 2.95-3.06 (m, 1H), 2.80 (d, 2H, J=8 Hz), 2.65-2.75 (m, 1H),2.36-2.54 (m, 2H), 2.01-2.13 (m, 1H), 2.05 (s, 3H), 1.72-1.92 (m, 4H),1.47-1.6 (m, 2H), 1.19-1.31 (m, 1H).

Step I: Preparation of N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester

N-(Piperidin-2(S)-ylmethyl)-N-(1-naphthylmethyl)glycyl-methionine methylester hydrochloride (2.1 g, 4 mmol), 4-imidazoleacetic acidhydrochloride (0.975 g, 6 mmol), hydroxybenzotriazole hydrate (0.811 g,6 mmol), EDC hydrochloride (1.15 g, 6 mmol) and TEA (2.23 mL, 16 mmol)were dissolved in dry DMF (25 mL) and stirred under Ar for 18 h. Themixture was concentrated in vacuo and the residue taken up in aq satdNaHCO₃ soln and extracted with EtOAc (2×100 mL). The organics werewashed with H₂ O and brine, dried over MgSO₄, filtered and the solventremoved in vacuo to give an oil which was chromatographed on silica gel(5:95 MeOH:CH₂ Cl₂), then further purified by preparative RPLC to givethe title compound as the trifluoroacetate salt. ¹ H NMR (CD₃ OD) δ8.87(d, 1H, J=1.5 Hz), 8.30-8.36 (m, 1H), 7.93-8.0 (m, 2H), 7.6-7.7 (m, 1H),7.47-7.6 (m, 3H), 7.40 (s, 1H), 4.95-5.05 (m, 1H), 4.4-4.8 (m, 2H),3.95-4.05 (m, 1H), 3.76-3.88 (m, 2H), 3.71 (s, 3H), 2.9-3.7 (m, 6H),2.28-2.5 (m, 2H), 2.0 (s, 3H), 1.95-2.1 (m, 1H), 1.75-1.9 (m, 1H),1.6-1.75 (m, 2H), 1.5-1.6 (m, 2H), 1.3-1.5 (m, 2H).

MS 566 (M+1).

Anal. Calcd for C₃₀ H₃₉ N₅ O₄ S.2.5 CF₃ CO₂ H: C, 49.44; H, 4.92; N,8.24. Found: C, 49.26; H, 4.98; N, 8.32.

Example 15 Preparation of N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

Step A: N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine

N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine (0.025 g, 0.032 mmol) was dissolved in CH₃ OH (1 mL)at ambient temperature, treated with 1N NaOH solution (0.128 mL, 0.128mmol) and stirred for 5 h. The solution was treated with 1N HCl (0.128mL, 0.128 mmol) and purified by preparative RP HPLC on a VYDAC columneluting with 1%TFA:H₂ O/1%TFA:CH₃ CN, 95:5 to 5:95 gradient to give thetitle compound as the trifluoroacetate salt. ¹ H NMR (CD₃ OD) δ8.87 (d,1H, J=1.5 Hz), 8.30-8.35(m, 1H), 7.93-8.02 (m, 2H), 7.66-7.73 (m, 1H),7.49-7.6 (m, 3H), 7.40 (s, 1H), 5.02-5.1 (m, 1H), 4.55-4.75 (m, 1H),4.45-4.55 (m, 1H), 3.4-4.1 (m, 8H), 3.05-3.25 (m, 1H), 2.3-2.5 (m, 2H),2.02 (s, 3H), 1.95-2.12 (m, 1H), 1.75-1.95 (m, 1H), 1.2-1.75 (m, 6H).

MS 552 (M+1).

Anal. Calcd for C₂₉ H₃₇ N₅ O₄ S.2 CF₃ CO₂ H.1. 15 CH₂ Cl₂ : C, 46.74; H,4.74; N, 7.98. Found: C, 46.60; H, 4.75; N, 8.35.

Example 16 Preparation of N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester

Following the procedures described in Example 1, but substitutingmethionine isopropyl ester hydrochloride for methionine methyl ester inStep G, the title compound was prepared.

MS 594 (M+1).

Anal. Calcd for C₃₂ H₄₃ N₅ O₄ S.2.8 CF₃ CO₂ H.0.3 H₂ O: C, 49.17; H,5.09; N, 7.63. Found: C, 49.16; H, 5.09; N, 7.51.

Example 17 Preparation of N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine

Following the procedures outlined in Examples 1 and 2, but substituting2-methoxybenzylalcohol for 1-naphthylmethanol in Example 1, Step D, thetitle compound was prepared.

MS 532 (M+1).

Anal. Calcd for C₂₆ H₃₇ N₅ O₅ S.3.25 CF₃ CO₂ H: C, 43.26; H, 4.50; N,7.76. Found: C, 43.23; H, 4.61; N, 7.86.

Example 18 Preparation of N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionineisopropyl ester

Following the procedures outlined in Example 1, but substituting2-methoxybenzyl alcohol for 1-naphthylmethanol in Step D, and methionineisopropyl ester hydrochloride for the methyl ester in Step G, the titlecompound was prepared.

MS 574 (M+1).

Anal. Calcd for C₂₉ H₄₃ N₅ O₅ S.2.35 CF₃ CO₂ H: C, 48.08; H, 5.43; N,8.32. Found: C, 48.12; H, 5.06; N, 8.58.

Example 19 Preparation of N-1-(1H-Imidazol-4-ylpropionyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester

Following the procedures outlined in Example 1, but substituting2-methoxybenzyl alcohol for 1-naphthylmethanol in Step D and4-imidazolepropionic acid for 4-imidazoleacetic acid in Step F, thetitle compound was prepared.

MS 560 (M+1).

Anal. Calcd for C₂₈ H₄₁ N₅ O₅ S: C, 60.08; H, 7.38; N, 12.51. Found: C,60.00; H, 7.25; N, 12.25.

Example 20 Preparation of N-1-(1H-Imidazol-4-ylpropionyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine

Following the procedures outlined in Example 2, but using the productfrom Example 6, the title compound was prepared.

MS 546 (M+1).

Anal. Calcd for C₂₇ H₃₉ N₅ O₅ S.3.0 CF₃ CO₂ H: C, 44.65; H, 4.77; N,7.89. Found: C, 44.41; H, 4.77; N, 8.19.

Example 21

In vitro inhibition of ras farnesyl transferase

Assays of farnesyl-protein transferase. Partially purified bovine FPTaseand Ras peptides (Ras-CVLS, Ras-CVIM and RAS-CAIL) were prepared asdescribed by Schaber et al., J. Biol. Chem. 265:14701-14704 (1990),Pompliano, et al., Biochemistry 31:3800 (1992) and Gibbs et al., PNASU.S.A. 86:6630-6634 (1989), respectively. Bovine FPTase was assayed in avolume of 100 μl containing 100 mM N-(2-hydroxy ethyl)piperazine-N'-(2-ethane sulfonic acid) (HEPES), pH 7.4, 5 mM MgCl₂, 5 mMdithiothreitol (DTT), 100 mM ³ H!-farnesyl diphosphate ( ³ H!-FPP; 740CBq/mmol, New England Nuclear), 650 nM Ras-CVLS and 10 μg/ml FPTase at31° C. for 60 min. Reactions were initiated with FPTase and stopped with1 ml of 1.0M HCL in ethanol. Precipitates were collected ontofilter-mats using a TomTec Mach II cell harvestor, washed with 100%ethanol, dried and counted in an LKB β-plate counter. The assay waslinear with respect to both substrates, FPTase levels and time; lessthan 10% of the ³ H!-FPP was utilized during the reaction period.Purified compounds were dissolved in 100% dimethyl sulfoxide (DMSO) andwere diluted 20-fold into the assay. Percentage inhibition is measuredby the amount of incorporation of radioactivity in the presence of thetest compound when compared to the amount of incorporation in theabsence of the test compound.

Human FPTase was prepared as described by Omer et al., Biochemistry32:5167-5176 (1993). Human FPTase activity was assayed as describedabove with the exception that 0.1% (w/v) polyethylene glycol 20,000, 10μM ZnCl₂ and 100 nM Ras-CVIM were added to the reaction mixture.Reactions were performed for 30 min., stopped with 100 μl of 30% (v/v)trichloroacetic acid (TCA) in ethanol and processed as described abovefor the bovine enzyme.

The compounds of the instant invention were tested for inhibitoryactivity against human FPTase by the assay described above and werefound to have IC₅₀ of <10 μM.

Example 22

In vivo ras farnesylation assay

The cell line used in this assay is a v-ras line derived from eitherRat1 or NIH3T3 cells, which expressed viral Ha-ras p21. The assay isperformed essentially as described in DeClue, J. E. et al., CancerResearch 51:712-717, (1991). Cells in 10 cm dishes at 50-75% confluencyare treated with the test compound (final concentration of solvent,methanol or dimethyl sulfoxide, is 0.1%). After 4 hours at 37° C., thecells are labelled in 3 ml methionine-free DMEM supple-meted with 10%regular DMEM, 2% fetal bovine serum and 400 mCi ³⁵ S!methionine (1000Ci/mmol). After an additional 20 hours, the cells are lysed in 1 mllysis buffer (1% NP40/20 mM HEPES, pH 7.5/5 mM MgCl₂ /1 mM DTT/10 mg/mlaprotinen/2 mg/ml leupeptin/2 mg/ml antipain/0.5 mM PMSF) and thelysates cleared by centrifugation at 100,000 ×g for 45 min. Aliquots oflysates containing equal numbers of acid-precipitable counts are boughtto 1 ml with IP buffer (lysis buffer lacking DTT) and immunoprecipitatedwith the ras-specific monoclonal antibody Y13-259 (Furth, M. E. et al.,J. Virol. 43:294-304, (1982)). Following a 2 hour antibody incubation at4° C., 200 ml of a 25% suspension of protein A-Sepharose coated withrabbit anti rat IgG is added for 45 min. The immunoprecipitates arewashed four times with IP buffer (20 nM HEPES, pH 7.5/1 mM EDTA/1%Triton X-100.0.5% deoxycholate/0.1%/SDS/0.1M NaCI) boiled in SDS-PAGEsample buffer and loaded on 13% acrylamide gels. When the dye frontreached the bottom, the gel is fixed, soaked in Enlightening, dried andautoradiographed. The intensities of the bands corresponding tofarnesylated and nonfarnesylated ras proteins are compared to determinethe percent inhibition of farnesyl transfer to protein.

Example 23

In vivo growth inhibition assay

To determine the biological consequences of FPTase inhibition, theeffect of the compounds of the instant invention on theanchorage-independent growth of Rat1 cells transformed with either av-ras, v-raf, or v-mos oncogene is tested. Cells transformed by v-Rafand v-Mos maybe included in the analysis to evaluate the specificity ofinstant compounds for Ras-induced cell transformation.

Rat 1 cells transformed with either v-ras, v-raf, or v-mos are seeded ata density of 1×10⁴ cells per plate (35 mm in diameter) in a 0.3% topagarose layer in medium A (Dulbecco's modified Eagle's mediumsupplemented with 10% fetal bovine serum) over a bottom agarose layer(0.6%). Both layers contain 0.1% methanol or an appropriateconcentration of the instant compound (dissolved in methanol at 1000times the final concentration used in the assay). The cells are fedtwice weekly with 0.5 ml of medium A containing 0.1% methanol or theconcentration of the instant compound. Photomicrographs are taken 16days after the cultures are seeded and comparisons are made.

What is claimed is:
 1. A compound which inhibits farnesyl-proteintransferase having the Formula I: ##STR62## wherein: R^(1a) and R^(1b)are independently selected from:a) hydrogen, b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkylunsubstituted or substituted by aryl, heterocyclic, C₃ -C₁₀ cycloalkyl,C₂ -C₆ alkenyl, C₂ -C₆ alkynl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)--NR¹⁰ --; R^(2a) and R^(2b) are independently selected from:a)hydrogen, b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocyclic and C₃ -C₁₀ cycloalkyl; R³ and R⁴ are independentlyselected from:a) a side chain of a naturally occurring amino acid, b) anoxidized form of a side chain of a naturally occurring amino acid whichis:i) methionine sulfoxide, or ii) methionine sulfone, and c)substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,wherein the substituent isselected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl; or R³ and R⁴ are combined toform --(CH₂)_(s) --; R^(5a) and R^(5b) are independently selectedfrom:a) a side chain of a naturally occurring amino acid, b) an oxidizedform of a side chain of a naturally occurring amino acid which is:i)methionine sulfoxide, or ii) methionine sulfone, c) substituted orunsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, arylor heterocycle group,wherein the substituent is selected from F, Cl, Br,CF₃, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ --and C₁ -C₂₀ alkyl, d) C₁ -C₆ alkyl substituted with an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl; or R^(5a) and R^(5b) are combined to form --(CH₂)_(s) --wherein one of the carbon atoms is optionally replaced by a moietyselected from: O, S(O)_(m), --NC(O)--, and --N(COR¹⁰)--; X--Y is##STR63## R^(7a) is selected from a) hydrogen,b) unsubstituted orsubstituted aryl, c) unsubstituted or substituted heterocycle, d)unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and e) C₁ -C₆ alkylsubstituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; R^(7b) isselected froma) hydrogen, b) unsubstituted or substituted aryl, c)unsubstituted or substituted heterocycle, d) unsubstituted orsubstituted C₃ -C₁₀ cycloalkyl, e) C₁ -C₆ alkyl substituted withhydrogen or an unsubstituted or substituted group selected from aryl,heterocycle and C₃ -C₁₀ cycloalkyl, f) a carbonyl group which is bondedto an unsubstituted or substituted group selected from aryl,heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkyl substituted withhydrogen or an unsubstituted or substituted group selected from aryl,heterocycle and C₃ -C₁₀ cycloalkyl, and g) a sulfonyl group which isbonded to an unsubstituted or substituted group selected from aryl,heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkyl substituted withhydrogen or an unsubstituted or substituted group selected from aryl,heterocycle and C₃ -C₁₀ cycloalkyl; R⁸ is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C--(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected from H, C₁-C₆ alkyl, benzyl, substituted aryl and C₁ -C₆ alkyl substituted withsubstituted aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; A¹ and A² are independently selected from: a bond, --CH═CH--,--C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--,--S(O)₂ N(R¹⁰)--, --N(R¹⁰)S(O)₂ --, or S(O)_(m) ; V is selected from:a)hydrogen, b) heterocycle, c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4carbon atoms are replaced with a a heteroatom selected from O, S, and N,and e) C₂ -C₂₀ alkenyl,provided that V is not hydrogen if A¹ is S(O)_(m)and V is not hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W isa heterocycle; Z is independently H₂ or O; ##STR64## or apharmaceutically acceptable salt thereof.
 2. A prodrug of a compoundhaving the Formula II: ##STR65## wherein: R^(1a) and R^(1b) areindependently selected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocyclic, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl,C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰--; R^(2a) and R^(2b) are independently selected from:a) hydrogen, b) C₁-C₆ alkyl unsubstituted or substituted by C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocyclic andC₃ -C₁₀ cycloalkyl; R³ and R⁴ are independently selected from:a) a sidechain of a naturally occurring amino acid, b) an oxidized form of a sidechain of a naturally occurring amino acid which is:i) methioninesulfoxide, or ii) methionine sulfone, c) substituted or unsubstituted C₁-C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclicgroup,wherein the substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl,and d) C₁ -C₆ alkyl substituted with an unsubstituted or substitutedgroup selected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or R³ andR⁴ are combined to form --(CH₂)_(s) --; R^(5a) and R^(5b) areindependently selected from:a) a side chain of a naturally occurringamino acid, b) an oxidized form of a side chain of a naturally occurringamino acid which is:i) methionine sulfoxide, or ii) methionine sulfone,c) substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocycle group,wherein the substituent isselected from F, Cl, Br, CF₃, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl; or R^(5a) and R^(5b) arecombined to form --(CH₂)_(s) -- wherein one of the carbon atoms isoptionally replaced by a moiety selected from: O, S(O)_(m), --NC(O)--,and --N(COR¹⁰)--; R⁶ isa) substituted or unsubstituted C₁ -C₈ alkyl,substituted or unsubstituted C₅ -C₈ cycloalkyl, or substituted orunsubstituted cyclic amine, wherein the substituted alkyl, cycloalkyl orcyclic amine is substituted with 1 or 2 substituents independentlyselected from:1) C₁ -C₆ alkyl, 2) aryl, 3) heterocycle, 4) --N(R¹¹)₂, 5)--OR¹⁰, or b) ##STR66## R^(7a) is selected from a) hydrogen, b)unsubstituted or substituted aryl, c) unsubstituted or substitutedheterocycle, d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and e)C₁ -C₆ alkyl substituted with hydrogen or an unsubstituted orsubstituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl; R^(7b) is selected froma) hydrogen, b) unsubstituted orsubstituted aryl, c) unsubstituted or substituted heterocycle, d)unsubstituted or substituted C₃ -C₁₀ cycloalkyl, e) C₁ -C₆ alkylsubstituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, f) a carbonylgroup which is bonded to an unsubstituted or substituted group selectedfrom aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkyl substitutedwith hydrogen or an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl, and g) a sulfonyl group whichis bonded to an unsubstituted or substituted group selected from aryl,heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkyl substituted withhydrogen or an unsubstituted or substituted group selected from aryl,heterocycle and C₃ -C₁₀ cycloalkyl; R⁸ is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected from H, C₁-C₆ alkyl, benzyl, substituted aryl and C₁ -C₆ alkyl substituted withsubstituted aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; R¹² is hydrogen or C₁ -C₆ alkyl; R¹³ is C₁ -C₆ alkyl; A¹ and A²are independently selected from: a bond, --CH═CH--, --C.tbd.C--,--C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ --, or S(O)_(m) ; V is selected from:a) hydrogen, b)heterocycle, c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atomsare replaced with a a heteroatom selected from O, S, and N, and e) C₂-C₂₀ alkenyl,provided that V is not hydrogen if A¹ is S(O)_(m) and V isnot hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is aheterocycle; Z is independently H₂ or O; ##STR67## or a pharmaceuticallyacceptable salt thereof.
 3. A compound which inhibits farnesyl-proteintransferase having the Formula III: ##STR68## wherein: R^(1a) and R^(1b)are independently selected from:a) hydrogen, b) aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkylunsubstituted or substituted by aryl, heterocyclic, C₃ -C₁₀ cycloalkyl,C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)--NR¹⁰ --; R^(2a) and R^(2b) are independently selected from:a)hydrogen, b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocyclic and C₃ -C₁₀ cycloalkyl; R³ and R⁴ are independentlyselected from:a) a side chain of a naturally occurring amino acid, b) anoxidized form of a side chain of a naturally occurring amino acid whichis:i) methionine sulfoxide, or ii) methionine sulfone, and c)substituted or unsubstituted C₁ -C₂₀ alkyl, C₂ -C₂₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocyclic group,wherein the substituent isselected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl; or R³ and R⁴ are combined toform --(CH₂)_(s) --; X--Y is ##STR69## R^(7a) is selected from a)hydrogen,b) unsubstituted or substituted aryl, c) unsubstituted orsubstituted heterocycle, d) unsubstituted or substituted C₃ -C₁₀cycloalkyl, and e) C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl; R^(7b) is selected froma) hydrogen, b) unsubstitutedor substituted aryl, c) unsubstituted or substituted heterocycle, d)unsubstituted or substituted C₃ -C₁₀ cycloalkyl, e) C₁ -C₆ alkylsubstituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, f) a carbonylgroup which is bonded to an unsubstituted or substituted group selectedfrom aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkyl substitutedwith hydrogen or an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl, and g) a sulfonyl group whichis bonded to an unsubstituted or substituted group selected from aryl,heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkyl substituted withhydrogen or an unsubstituted or substituted group selected from aryl,heterocycle and C₃ -C₁₀ cycloalkyl; R⁸ is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C--(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected from H, C₁-C₆ alkyl, benzyl, substituted aryl and C₁ -C₆ alkyl substituted withsubstituted aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; R¹² is hydrogen or C₁ -C₆ alkyl; R¹³ is C₁ -C₆ alkyl; A¹ and A²are independently selected from: a bond, --CH═CH--, --C.tbd.C--,--C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ --, or S(O)_(m) ; V is selected from:a) hydrogen, b)heterocycle, c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atomsare replaced with a a heteroatom selected from O, S, and N, and e) C₂-C₂₀ alkenyl,provided that V is not hydrogen if A¹ is S(O)_(m) and V isnot hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is aheterocycle; Z is independently H₂ or O; ##STR70## or a pharmaceuticallyacceptable salt thereof.
 4. A prodrug of a compound of claim 3 of theFormula IV: ##STR71## wherein: R^(1a) and R^(1b) are independentlyselected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂-C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, R¹⁰O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)--NR¹⁰ --; R^(2a) andR^(2b) are independently selected from:a) hydrogen, b) C₁ -C₆ alkylunsubstituted or substituted by C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹ S(O)_(m)--, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; c) aryl, heterocycle, C₃ -C₁₀cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkyl substituted with an unsubstitutedor substituted group selected from aryl, heterocyclic and C₃ -C₁₀cycloalkyl; R³ and R⁴ are independently selected from:a) a side chain ofa naturally occurring amino acid, b) an oxidized form of a side chain ofa naturally occurring amino acid which is:i) methionine sulfoxide, orii) methionine sulfone, c) substituted or unsubstituted C₁ -C₂₀ alkyl,C₂ -C₂₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocycle group,whereinthe substituent is selected from F, Cl, Br, N(R¹⁰)₂, NO₂, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁-C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; or R³ and R⁴ arecombined to form --(CH₂)_(s) --; X--Y is ##STR72## R^(7a) is selectedfrom a) hydrogen,b) unsubstituted or substituted aryl, c) unsubstitutedor substituted heterocycle, d) unsubstituted or substituted C₃ -C₁₀cycloalkyl, and e) C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl; R^(7b) is selected froma) hydrogen, b) unsubstitutedor substituted aryl, c) unsubstituted or substituted heterocycle, d)unsubstituted or substituted C₃ -C₁₀ cycloalkyl, e) C₁ -C₆ alkylsubstituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, f) a carbonylgroup which is bonded to an unsubstituted or substituted group selectedfrom aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkyl substitutedwith hydrogen or an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl, and g) a sulfonyl group whichis bonded to an unsubstituted or substituted group selected from aryl,heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkyl substituted withhydrogen or an unsubstituted or substituted group selected from aryl,heterocycle and C₃ -C₁₀ cycloalkyl; R⁸ is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, R¹⁰ ₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NH--, CN, H₂ N--C(NH)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, orR¹⁰ OC(O)NH--; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂-C₆ alkynyl, perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by perfluoroalkyl, F, Cl, Br, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected from H, C₁-C₆ alkyl, benzyl, substituted aryl and C₁ -C₆ alkyl substituted withsubstituted aryl; R¹¹ is independently selected from C₁ -C₆ alkyl andaryl; R¹² is hydrogen or C₁ -C₆ alkyl; R¹³ is C₁ -C₆ alkyl; A¹ and A²are independently selected from: a bond, --CH═CH--, --C.tbd.C--,--C(O)--, --C(O)NR¹⁰ --, --NR¹⁰ C(O)--, O, --N(R¹⁰)--, --S(O)₂ N(R¹⁰)--,--N(R¹⁰)S(O)₂ --, or S(O)_(m) ; V is selected from:a) hydrogen, b)heterocycle, c) aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atomsare replaced with a a heteroatom selected from O, S, and N, and e) C₂-C₂₀ alkenyl,provided that V is not hydrogen if A¹ is S(O)_(m) and V isnot hydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is aheterocycle; Z is independently H₂ or O; ##STR73## or a pharmaceuticallyacceptable salt thereof.
 5. The compound according to claim 1 of theformula I: ##STR74## wherein: R^(1a) is independently selected from:hydrogen or C₁ -C₆ alkyl;R^(1b) is independently selected from:a)hydrogen, b) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂or alkenyl, c) C₁ -C₆ alkyl unsubstituted or substituted by aryl,heterocycle, cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ; R^(2a) isselected from:a) hydrogen, b) C₁ -C₆ alkyl unsubstituted or substitutedby C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁-C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl; R^(2b) ishydrogen; R³ and R⁴ are independently selected from:a) a side chain of anaturally occurring amino acid, b) an oxidized form of a side chain of anaturally occurring amino acid which is:i) methionine sulfoxide, or ii)methionine sulfone, c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂-C₁₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclic group,wherein thesubstituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl; R^(5a) is selected from:a) aside chain of a naturally occurring amino acid, wherein the amino acidis selected from methionine and glutamine, b) an oxidized form of a sidechain of a naturally occurring amino acid which is:i) methioninesulfoxide, or ii) methionine sulfone, and c) substituted orunsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀ cycloalkyl, arylor heterocyclic group,wherein the substituent is selected from F, Cl,Br, CF₃, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ --and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkyl substituted with an unsubstitutedor substituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl; R^(5b) is selected from:a) hydrogen, and b) C₁ -C₃ alkyl;X--Y is ##STR75## R^(7a) is selected from a) hydrogen,b) unsubstitutedor substituted aryl, c) unsubstituted or substituted heterocycle, d)unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and e) C₁ -C₆ alkylsubstituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;whereinheterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl; R^(7b) is selected froma) hydrogen, b)unsubstituted or substituted aryl, c) unsubstituted or substitutedheterocycle, d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl, e) C₁-C₆ alkyl substituted with hydrogen or an unsubstituted or substitutedgroup selected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, f) acarbonyl group which is bonded to an unsubstituted or substituted groupselected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkylsubstituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, and g) asulfonyl group which is bonded to an unsubstituted or substituted groupselected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkylsubstituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl; whereinheterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl; R⁸ is independently selected from:a)hydrogen, b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, andc) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; A¹ and A² are independently selected from: abond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c)aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a a heteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is nothydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is a heterocycleselected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z isindependently H₂ or O; ##STR76## or a pharmaceutically acceptable saltthereof.
 6. The compound according to claim 1 of the formula I:##STR77## wherein: R^(1a) is independently selected from: hydrogen or C₁-C₆ alkyl;R^(1b) is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆ alkenyl,c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle, C₃-C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ; R^(2a) isselected from:a) hydrogen, b) C₁ -C₆ alkyl unsubstituted or substitutedby C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃,(R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹OC(O)NR¹⁰ --, c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl,R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--,R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁-C₆ alkyl substituted with an unsubstituted or substituted groupselected from aryl, heterocyclic and C₃ -C₁₀ cycloalkyl; R^(2b) ishydrogen; R³ and R⁴ are independently selected from:a) a side chain of anaturally occurring amino acid, b) an oxidized form of a side chain of anaturally occurring amino acid which is:i) methionine sulfoxide, or ii)methionine sulfone, c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂-C₁₀ alkenyl, C₃ -C₁₀ cycloalkyl, aryl or heterocyclic group,wherein thesubstituent is selected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃,--N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocycle and C₃ -C₁₀ cycloalkyl; R^(5a) is selected from:a) aside chain of a naturally occurring amino acid, wherein the amino acidis selected from methionine and glutamine, b) an oxidized form of a sidechain of a naturally occurring amino acid which is:i) methioninesulfoxide, or ii) methionine sulfone, and c) substituted orunsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀ cycloalkyl, arylor heterocyclic group,wherein the substituent is selected from F, Cl,Br, CF₃, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹ OC(O)NR¹⁰ --and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkyl substituted with an unsubstitutedor substituted group selected from aryl, heterocycle and C₃ -C₁₀cycloalkyl; R^(5b) is selected from:a) hydrogen, and b) C₁ -C₃ alkyl; R⁶isa) substituted or unsubstituted C₁ -C₈ alkyl, substituted orunsubstituted C₅ -C₈ cycloalkyl, or substituted or unsubstituted cyclicamine, wherein the substituted alkyl, cycloalkyl or cyclic amine issubstituted with 1 or 2 substituents independently selected from:1) C₁-C₆ alkyl, 2) aryl, 3) heterocycle, 4) --N(R¹¹)₂, 5) --OR¹⁰, or##STR78## R^(7a) is selected from a) hydrogen, b) unsubstituted orsubstituted aryl, c) unsubstituted or substituted heterocycle, d)unsubstituted or substituted C₃ -C₁₀ cycloalkyl, and e) C₁ -C₆ alkylsubstituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;whereinheterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl; R^(7b) is selected froma) hydrogen, b)unsubstituted or substituted aryl, c) unsubstituted or substitutedheterocycle, d) unsubstituted or substituted C₃ -C₁₀ cycloalkyl, e) C₁-C₆ alkyl substituted with hydrogen or an unsubstituted or substitutedgroup selected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, f) acarbonyl group which is bonded to an unsubstituted or substituted groupselected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkylsubstituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl, and g) asulfonyl group which is bonded to an unsubstituted or substituted groupselected from aryl, heterocycle, C₃ -C₁₀ cycloalkyl and C₁ -C₆ alkylsubstituted with hydrogen or an unsubstituted or substituted groupselected from aryl, heterocycle and C₃ -C₁₀ cycloalkyl;whereinheterocycle is selected from pyrrolidinyl, imidazolyl, pyridinyl,thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl, quinolinyl,isoquinolinyl, and thienyl; R⁸ is independently selected from:a)hydrogen, b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁ -C₆perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; R¹² is hydrogen or C₁ -C₆ alkyl; R¹³ is1,1-dimethylethyl; A¹ and A² are independently selected from: a bond,--CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c)aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a a heteroatom selected from O, S, and N, e) C₂ -C₂₀ alkenyl,andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is nothydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is a heterocycleselected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z isindependently H₂ or O; ##STR79## or a pharmaceutically acceptable saltthereof.
 7. The compound according to claim 1 of the formula I:##STR80## wherein: R^(1a) is independently selected from: hydrogen or C₁-C₆ alkyl;R^(1b) is independently selected from:a) hydrogen, b) aryl,heterocycle, C₃ -C₁₀ cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆ alkenyl,c) C₁ -C₆ alkyl unsubstituted or substituted by aryl, heterocycle,cycloalkyl, alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ; R^(2a) is selected from:a)hydrogen, b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocyclic and C₃ -C₁₀ cycloalkyl; R^(2b) is hydrogen; R³ and R⁴are independently selected from:a) a side chain of a naturally occurringamino acid, b) an oxidized form of a side chain of a naturally occurringamino acid which is:i) methionine sulfoxide, or ii) methionine sulfone,c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocycle group,wherein the substituent isselected from F, Cl, Br, --NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰--, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl; X--Y is ##STR81## R^(7a) is selected from a)hydrogen,b) unsubstituted or substituted aryl, c) unsubstituted orsubstituted heterocycle, d) unsubstituted or substituted C₃ -C₁₀cycloalkyl, and e) C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl;wherein heterocycle is selected from pyrrolidinyl,imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,quinolinyl, isoquinolinyl, and thienyl; R^(7b) is selected froma)hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted orsubstituted heterocycle, d) unsubstituted or substituted C₃ -C₁₀cycloalkyl, e) C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl, f) a carbonyl group which is bonded to anunsubstituted or substituted group selected from aryl, heterocycle, C₃-C₁₀ cycloalkyl and C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl, and g) a sulfonyl group which is bonded to anunsubstituted or substituted group selected from aryl, heterocycle, C₃-C₁₀ cycloalkyl and C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl;wherein heterocycle is selected from pyrrolidinyl,imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,quinolinyl, isoquinolinyl, and thienyl; R⁸ is independently selectedfrom:a) hydrogen, b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; A¹ and A² are independently selected from: abond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c)aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a a heteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is nothydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is a heterocycleselected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z isindependently H₂ or O; ##STR82## or a pharmaceutically acceptable saltthereof.
 8. A compound of formula IV: ##STR83## wherein: R^(1a) isindependently selected from: hydrogen or C₁ -C₆ alkyl;R^(1b) isindependently selected from:a) hydrogen, b) aryl, heterocycle, C₃ -C₁₀cycloalkyl, R¹⁰ O--, --N(R¹⁰)₂ or C₂ -C₆ alkenyl, c) C₁ -C₆ alkylunsubstituted or substituted by aryl, heterocycle, C₃ -C₁₀ cycloalkyl,C₂ -C₆ alkenyl, R¹⁰ O--, or --N(R¹⁰)₂ ; R^(2a) is selected from:a)hydrogen, b) C₁ -C₆ alkyl unsubstituted or substituted by C₂ -C₆alkenyl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, N₃, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,c) aryl, heterocycle, C₃ -C₁₀ cycloalkyl, C₂ -C₆ alkenyl, R¹⁰ O--, R¹¹S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--,R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and d) C₁ -C₆ alkylsubstituted with an unsubstituted or substituted group selected fromaryl, heterocyclic and C₃ -C₁₀ cycloalkyl; R^(2b) is hydrogen; R³ and R⁴are independently selected from:a) a side chain of a naturally occurringamino acid, b) an oxidized form of a side chain of a naturally occurringamino acid which is:i) methionine sulfoxide, or ii) methionine sulfone,c) substituted or unsubstituted C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₃ -C₁₀cycloalkyl, aryl or heterocycle group,wherein the substituent isselected from F, Cl, Br, NO₂, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰ C(O)NR¹⁰ --,CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, N₃, --N(R¹⁰)₂, R¹¹OC(O)NR¹⁰ -- and C₁ -C₂₀ alkyl, and d) C₁ -C₆ alkyl substituted with anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl; X--Y is ##STR84## R^(7a) is selected from a)hydrogen,b) unsubstituted or substituted aryl, c) unsubstituted orsubstituted heterocycle, d) unsubstituted or substituted C₃ -C₁₀cycloalkyl, and e) C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl;wherein heterocycle is selected from pyrrolidinyl,imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,quinolinyl, isoquinolinyl, and thienyl; R^(7b) is selected froma)hydrogen, b) unsubstituted or substituted aryl, c) unsubstituted orsubstituted heterocycle, d) unsubstituted or substituted C₃ -C₁₀cycloalkyl, e) C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl, f) a carbonyl group which is bonded to anunsubstituted or substituted group selected from aryl, heterocycle, C₃-C₁₀ cycloalkyl and C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl, and g) a sulfonyl group which is bonded to anunsubstituted or substituted group selected from aryl, heterocycle, C₃-C₁₀ cycloalkyl and C₁ -C₆ alkyl substituted with hydrogen or anunsubstituted or substituted group selected from aryl, heterocycle andC₃ -C₁₀ cycloalkyl;wherein heterocycle is selected from pyrrolidinyl,imidazolyl, pyridinyl, thiazolyl, pyridonyl, 2-oxopiperidinyl, indolyl,quinolinyl, isoquinolinyl, and thienyl; R⁸ is independently selectedfrom:a) hydrogen, b) C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₁-C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹⁰ C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --,and c) C₁ -C₆ alkyl substituted by C₁ -C₆ perfluoroalkyl, R¹⁰ O--, R¹⁰C(O)NR¹⁰ --, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--, --N(R¹⁰)₂, orR¹¹ OC(O)NR¹⁰ --; R⁹ is selected from:a) hydrogen, b) C₂ -C₆ alkenyl, C₂-C₆ alkynyl, C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --, R¹⁰C(O)NR¹⁰ --, CN, NO₂, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --, and c) C₁ -C₆ alkyl unsubstituted orsubstituted by C₁ -C₆ perfluoroalkyl, F, Cl, R¹⁰ O--, R¹¹ S(O)_(m) --,R¹⁰ C(O)NR¹⁰ --, CN, (R¹⁰)₂ N--C(NR¹⁰)--, R¹⁰ C(O)--, R¹⁰ OC(O)--,--N(R¹⁰)₂, or R¹¹ OC(O)NR¹⁰ --; R¹⁰ is independently selected fromhydrogen, C₁ -C₆ alkyl, benzyl and aryl; R¹¹ is independently selectedfrom C₁ -C₆ alkyl and aryl; A¹ and A² are independently selected from: abond, --CH═CH--, --C.tbd.C--, --C(O)--, --C(O)NR¹⁰ --, O, --N(R¹⁰)--, orS(O)_(m) ; V is selected from:a) hydrogen, b) heterocycle selected frompyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, isoquinolinyl, and thienyl, c)aryl, d) C₁ -C₂₀ alkyl wherein from 0 to 4 carbon atoms are replacedwith a a heteroatom selected from O, S, and N, and e) C₂ -C₂₀ alkenyl,andprovided that V is not hydrogen if A¹ is S(O)_(m) and V is nothydrogen if A¹ is a bond, n is 0 and A² is S(O)_(m) ; W is a heterocycleselected from pyrrolidinyl, imidazolyl, pyridinyl, thiazolyl, pyridonyl,2-oxopiperidinyl, indolyl, quinolinyl, or isoquinolinyl; Z isindependently H₂ or O; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; p is 0, 1,2, 3 or 4; q is 0, 1 or 2; r is 0 to 5, provided that r is 0 when V ishydrogen; t is 4; and u is 0 or 1;or a pharmaceutically acceptable saltthereof.
 9. A compound which inhibits farnesyl-protein transferase whichis:N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methioninemethyl ester; N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionine;N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(1-naphthylmethyl)glycyl-methionineisopropyl ester; N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine;N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionineisopropyl ester; N-1-(1H-Imidazol-4-ylpropionyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methioninemethyl ester; N-1-(1H-Imidazol-4-ylpropionyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine;ora pharmaceutically acceptable salt thereof.
 10. The compound accordingto claim 9 which inhibits farnesyl-protein transferase which is:N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionine##STR85## or a pharmaceutically acceptable salt thereof.
 11. Thecompound according to claim 9 which inhibits farnesyl-proteintransferase which is:N-1-(1H-Imidazol-4-ylacetyl)piperidin-2(S)-ylmethyl!-N-(2-methoxybenzyl)glycyl-methionineisopropyl ester ##STR86## or a pharmaceutically acceptable salt thereof.12. A pharmaceutical composition comprising a pharmaceutical carrier,and dispersed therein, a therapeutically effective amount of a compoundof claim
 1. 13. A pharmaceutical composition comprising a pharmaceuticalcarrier, and dispersed therein, a therapeutically effective amount of acompound of claim
 2. 14. A pharmaceutical composition comprising apharmaceutical carrier, and dispersed therein, a therapeuticallyeffective amount of a compound of claim
 3. 15. A pharmaceuticalcomposition comprising a pharmaceutical carrier, and dispersed therein,a therapeutically effective amount of a compound of claim
 4. 16. Apharmaceutical composition comprising a pharmaceutical carrier, anddispersed therein, a therapeutically effective amount of a compound ofclaim
 9. 17. A method for inhibiting farnesyl-protein transferase whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of the composition of claim
 12. 18. A method forinhibiting farnesyl-protein transferase which comprises administering toa mammal in need thereof a therapeutically effective amount of thecomposition of claim
 13. 19. A method for inhibiting farnesyl-proteintransferase which comprises administering to a mammal in need thereof atherapeutically effective amount of the composition of claim
 14. 20. Amethod for inhibiting farnesyl-protein transferase which comprisesadministering to a mammal in need thereof a therapeutically effectiveamount of the composition of claim
 15. 21. A method for inhibitingfarnesyl-protein transferase which comprises administering to a mammalin need thereof a therapeutically effective amount of the composition ofclaim
 16. 22. A method for treating cancer which comprises administeringto a mammal in need thereof a therapeutically effective amount of acomposition of claim
 12. 23. A method for treating cancer whichcomprises administering to a mammal in need thereof a therapeuticallyeffective amount of a composition of claim
 13. 24. A method for treatingcancer which comprises administering to a mammal in need thereof atherapeutically effective amount of a composition of claim
 14. 25. Amethod for treating cancer which comprises administering to a mammal inneed thereof a therapeutically effective amount of a composition ofclaim
 16. 26. A method for treating cancer which comprises administeringto a mammal in need thereof a therapeutically effective amount of acomposition of claim 16.